Aging Cell最新文献_第8页

Investigating the Role of TRPV4 and GPR35 Interaction in Endothelial Dysfunction in Aging Mice 研究TRPV4和GPR35相互作用在衰老小鼠内皮功能障碍中的作用。

IF 7.8 1区医学

Aging Cell Pub Date : 2025-01-02 DOI: 10.1111/acel.14469

Xiaoxue Tian, Hao Kan, Liu Yang, Zhiwei Wang, Tiantian Zhang, Ka Zhang, Aiqin Mao, Xin Wen, Tingting Zhou, Xiaoyan Wang, Xiaodong Zhang, Lei Feng, Li Geng

{"title":"Investigating the Role of TRPV4 and GPR35 Interaction in Endothelial Dysfunction in Aging Mice","authors":"Xiaoxue Tian, Hao Kan, Liu Yang, Zhiwei Wang, Tiantian Zhang, Ka Zhang, Aiqin Mao, Xin Wen, Tingting Zhou, Xiaoyan Wang, Xiaodong Zhang, Lei Feng, Li Geng","doi":"10.1111/acel.14469","DOIUrl":"10.1111/acel.14469","url":null,"abstract":"Endothelial dysfunction, characterized by a decline in endothelial physiological functions, is a significant aspect of cardiovascular aging, contributing notably to arterial stiffness, atherosclerosis, and hypertension. Transient receptor potential channel V4 (TRPV4), a key member of Ca2+-permeable channels, plays a crucial role in maintaining vascular functions. However, the role and mechanisms of TRPV4 in aging-related endothelial dysfunction remain incompletely understood. Here, we demonstrated a marked reduction in endothelial TRPV4 function without alterations in its expression, leading to abnormal endothelial Ca2+ signaling and impaired vasodilation in aging mesenteric arteries. Employing transcriptome sequencing, co-IP, and PLA assays, we characterized G protein-coupled receptor 35 (GPR35) interacting with TRPV4, and abnormally enhanced interactions were found in aging endothelial cells. Subsequently, we revealed that intensive GPR35-TRPV4 interaction significantly contributes to endothelial dysfunction during aging, utilizing TRPV4 endothelial-specific knockout (TRPV4EC−/−), AAV-FLT1-shRNA (GPR35) mice, and GPR35 overexpressed/knocked-down HUVECs. Furthermore, molecular docking analysis and subsequent co-IP and pressure myograph experiments indicated that both Thonningianin A and Carfilzomib efficiently restored the GPR35-TRPV4 interaction, preventing endothelial dysfunction and vasodilation impairment. Our study identifies the crucial role of GPR35-TRPV4 interaction in aging-associated abnormal endothelial function and vascular tone modulation. Restoring GPR35-TRPV4 interaction via Thonningianin A or Carfilzomib represents a promising precision approach for aging-related endothelial dysfunction.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 5","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14469","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF 7.8 1区医学

Aging Cell Pub Date : 2025-01-02 DOI: 10.1111/acel.14460

Mingyan Fang, Yu Miao, Lin Zhu, Yunpeng Mei, Hui Zeng, Lihua Luo, Yuan Ding, Lina Zhou, Xueping Quan, Qin Zhao, Xiaodong Zhao, Yunfei An

{"title":"Age-Related Dynamics and Spectral Characteristics of the TCRβ Repertoire in Healthy Children: Implications for Immune Aging","authors":"Mingyan Fang, Yu Miao, Lin Zhu, Yunpeng Mei, Hui Zeng, Lihua Luo, Yuan Ding, Lina Zhou, Xueping Quan, Qin Zhao, Xiaodong Zhao, Yunfei An","doi":"10.1111/acel.14460","DOIUrl":"10.1111/acel.14460","url":null,"abstract":"T-cell receptor (TCR) diversity is crucial for adaptive immunity, yet baseline characterizations in pediatric populations remain sparse. We sequenced the TCRβ chain of 325 healthy Chinese children aged 0–18, categorized into six age groups. We also analyzed cellular composition and TCRβ associations using flow cytometry in 81 of these samples. Our results indicate a decrease in TCRβ diversity with age, characterized by an increase in high-frequency clonotypes and notable changes in CDR3 length and V(D)J gene usage. These changes are influenced by early life vaccinations and antigen exposures. Additionally, we found a significant association between reduced TCRβ diversity and a decrease in CD4+ T naïve cells. We also developed a predictive model that identifies specific TCRβ features as potential biomarkers for biological age, validated by their significant correlation with changes in the immune repertoire. These findings enhance our understanding of age-related variations in the TCRβ repertoire among children, providing resourceful information for research on pediatric TCR in health and disease.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 4","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14460","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CALB1 and RPL23 Are Essential for Maintaining Oocyte Quality and Function During Aging CALB1和RPL23对维持衰老过程中卵母细胞的质量和功能至关重要。

IF 7.8 1区医学

Aging Cell Pub Date : 2025-01-02 DOI: 10.1111/acel.14466

Yingxue Han, Zihuan Du, Hao Wu, Rong Zhao, Jikang Liu, Shuai Gao, Shenming Zeng

{"title":"CALB1 and RPL23 Are Essential for Maintaining Oocyte Quality and Function During Aging","authors":"Yingxue Han, Zihuan Du, Hao Wu, Rong Zhao, Jikang Liu, Shuai Gao, Shenming Zeng","doi":"10.1111/acel.14466","DOIUrl":"10.1111/acel.14466","url":null,"abstract":"With advancing age, significant changes occur in the female reproductive system, the most notable of which is the decline in oocyte quality, a key factor affecting female fertility. However, the mechanisms underlying oocyte aging remain poorly understood. In this study, we obtained oocytes from aged and young female mice and performed single-cell transcriptome sequencing, comparing our findings with existing proteomic analyses. Our analysis revealed that one of the primary characteristics of aging oocytes is the disruption of calcium ion homeostasis. Specifically, we identified two key genes involved in the oocyte aging process, Calb1 and Rpl23. Experimental validation demonstrated that knockdown of CALB1 in oocytes led to reduced calcium ion levels in the endoplasmic reticulum and mitochondria, resulting in mitochondrial dysfunction and meiotic defects. Further experiments suggested that RPL23 may function as a downstream gene of CALB1, and its knockdown caused mitochondrial dysfunction, excessive accumulation of reactive oxygen species (ROS), and spindle assembly defects. Notably, overexpression of these two genes in aging oocytes partially rescued the maternal age-related defective phenotypes, underscoring their crucial roles in oocyte aging. This study provides a comprehensive understanding of the specific mechanisms underlying mouse oocyte aging at single-cell resolution, supported by experimental validation, and offers new directions and potential targets for future research into age-related reproductive health issues.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 5","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identifying ENO1 as a protein target of chlorogenic acid to inhibit cellular senescence and prevent skin photoaging in mice 确定ENO1作为绿原酸抑制细胞衰老和防止小鼠皮肤光老化的蛋白靶点。

IF 7.8 1区医学

Aging Cell Pub Date : 2024-12-31 DOI: 10.1111/acel.14433

Xueling He, Chen Wang, Qianyu Zhang, Tong Yang, Qiuyan Guo, Yaxu Wang, Jiayue Guo, Pengjie Wang, Junzhe Zhang, Huan Tang, Yinhua Zhu, Jigang Wang

{"title":"Identifying ENO1 as a protein target of chlorogenic acid to inhibit cellular senescence and prevent skin photoaging in mice","authors":"Xueling He, Chen Wang, Qianyu Zhang, Tong Yang, Qiuyan Guo, Yaxu Wang, Jiayue Guo, Pengjie Wang, Junzhe Zhang, Huan Tang, Yinhua Zhu, Jigang Wang","doi":"10.1111/acel.14433","DOIUrl":"10.1111/acel.14433","url":null,"abstract":"Cellular senescence plays a critical role in repeated ultraviolet (UV) exposure-induced skin photoaging. Currently, from the perspective of regulating senescent cells, potent compounds or reliable protein targets that could effectively prevent skin photoaging have not yet been reported. Herein, we demonstrated that chlorogenic acid (CGA) significantly inhibited UVA-induced senescence of human dermis skin fibroblasts (HDF) cells by screening the natural product library. The activity-based protein profiling (ABPP) result revealed that Enolase 1 (ENO1) is one of the direct targets of CGA in HDF cells. Further mechanism research indicated that CGA covalently binds to ENO1, and prevented UVA-induced cellular senescence by suppressing the activity of ENO1 protein to block the glycolytic pathway. Importantly, we found that CGA dose-dependently reduced the skin wrinkle score, alleviated skin pathological features and inhibited senescent characteristics in a photoaging mouse model. The proteomic analysis revealed that CGA treatment effectively inhibited senescence-associated secretory phenotype (SASP) secretion and glycolysis in skin samples of mice. Collectively, our study not only demonstrated that inhibiting cell senescence is an effective anti-skin photoaging strategy, but also revealed that ENO1 is a promising protein target to prevent photoaging.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 4","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14433","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

P2Y2 Inhibition Modifies the Anabolic Response to Exercise in Adult Mice P2Y2抑制改变成年小鼠对运动的合成代谢反应。

IF 7.8 1区医学

Aging Cell Pub Date : 2024-12-31 DOI: 10.1111/acel.14464

Amit Chougule, Chunbin Zhang, Jordan Denbow, Nickolas Vinokurov, Devin Mendez, Elizabeth Vojtisek, Joseph Gardinier

{"title":"P2Y2 Inhibition Modifies the Anabolic Response to Exercise in Adult Mice","authors":"Amit Chougule, Chunbin Zhang, Jordan Denbow, Nickolas Vinokurov, Devin Mendez, Elizabeth Vojtisek, Joseph Gardinier","doi":"10.1111/acel.14464","DOIUrl":"10.1111/acel.14464","url":null,"abstract":"As the aging population continues to grow, the incidence of osteoporotic fractures increases and is compounded by our lack of therapeutic strategies that increase bone formation. Although exercise and physical activity play a key role in maintaining bone mass throughout our lives, the loads and exertion required to elicit an anabolic response becomes exceedingly difficult to achieve with age. Based on previous work, the P2Y2 receptor offers a unique therapeutic target to increasing bone mass by modifying the mechanotransduction. Others have also shown P2Y2 to have a negative effect on osteoblast function. However, the extent to which inhibiting P2Y2 pharmaceutically improves bone mass or the mechanotransduction of bone remains unknown. Our central hypothesis for this study states that inhibiting P2Y2 activity can enhance the anabolic response to loading in an aging population. To test this hypothesis, the anabolic response to exercise was examined by treating adult mice, which typically display a minimal response, with the P2Y2 inhibitor AR-C118925XX (ARC). Our findings from this study demonstrate that ARC treatment of adult mice increases periosteal bone formation in response to exercise. The enhanced response to exercise was characterized by a reduction in osteocytes' induction of osteoclast activity. Endocortical bone formation also increased with treatment independently of exercise, providing gains in mechanical strength and tissue level properties. Overall, inhibiting P2Y2 activation has a beneficial effect on bone formation and the anabolic response to loading, namely by limiting osteoclast activation.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 5","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14464","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of Aging on Glucose and Lipid Metabolism in Mice 衰老对小鼠糖脂代谢的影响。

IF 7.8 1区医学

Aging Cell Pub Date : 2024-12-27 DOI: 10.1111/acel.14462

Evan C. Lien, Ngoc Vu, Anna M. Westermark, Laura V. Danai, Allison N. Lau, Yetiş Gültekin, Matthew A. Kukurugya, Bryson D. Bennett, Matthew G. Vander Heiden

{"title":"Effects of Aging on Glucose and Lipid Metabolism in Mice","authors":"Evan C. Lien, Ngoc Vu, Anna M. Westermark, Laura V. Danai, Allison N. Lau, Yetiş Gültekin, Matthew A. Kukurugya, Bryson D. Bennett, Matthew G. Vander Heiden","doi":"10.1111/acel.14462","DOIUrl":"10.1111/acel.14462","url":null,"abstract":"Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 4","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14462","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epidermal Collagen Reduction Drives Selective Aspects of Aging in Sensory Neurons 表皮胶原蛋白减少驱动感觉神经元选择性老化。

IF 7.8 1区医学

Aging Cell Pub Date : 2024-12-27 DOI: 10.1111/acel.14459

Meera M. Krishna, Swapnil G. Waghmare, Ariel L. Franitza, Emily C. Maccoux, Lezi E

{"title":"Epidermal Collagen Reduction Drives Selective Aspects of Aging in Sensory Neurons","authors":"Meera M. Krishna, Swapnil G. Waghmare, Ariel L. Franitza, Emily C. Maccoux, Lezi E","doi":"10.1111/acel.14459","DOIUrl":"10.1111/acel.14459","url":null,"abstract":"Despite advances in understanding molecular and cellular changes in the aging nervous system, the upstream drivers of these changes remain poorly defined. Here, we investigate the roles of non-neural tissues in neuronal aging, using the cutaneous PVD polymodal sensory neuron in Caenorhabditis elegans as a model. We demonstrate that during normal aging, PVD neurons progressively develop excessive dendritic branching, functionally correlated with age-related proprioceptive deficits. Our study reveals that decreased collagen expression, a common age-related phenomenon across species, triggers this process. Specifically, loss-of-function in dpy-5 or col-120, genes encoding cuticular collagens secreted to the epidermal apical surface, induces early-onset excessive dendritic branching and proprioceptive deficits. Adulthood-specific overexpression of dpy-5 or col-120 mitigates excessive branching in aged animals without extending lifespan, highlighting their specific roles in promoting neuronal health span. Notably, collagen reduction specifically drives excessive branching in select sensory neuron subclasses but does not contribute to PVD dendritic beading, another aging-associated neurodegenerative phenotype associated with distinct mechanosensitive dysfunction. Lastly, we identify that rig-3, an immunoglobulin superfamily member expressed in interneurons, acts upstream of collagen genes to maintain PVD dendritic homeostasis during aging, with collagen's regulatory role requiring daf-16/FOXO. These findings reveal that age-related collagen reduction cues neuronal aging independently of collagen's traditional structural support function, possibly involving bi-directional communication processes between neurons and non-neuronal cells. Our study also offers new insights into understanding selective neuron vulnerability in aging, emphasizing the importance of multi-tissue strategies to address the complexities of neuronal aging.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 4","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14459","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nuclear respiratory factor-1 (NRF1) induction as a powerful strategy to deter mitochondrial dysfunction and senescence in mesenchymal stem cells 核呼吸因子-1 （NRF1）诱导是阻止间充质干细胞线粒体功能障碍和衰老的有效策略。

IF 7.8 1区医学

Aging Cell Pub Date : 2024-12-25 DOI: 10.1111/acel.14446

Hyunho Lee, Matteo Massaro, Nourhan Abdelfattah, Gherardo Baudo, Haoran Liu, Kyuson Yun, Elvin Blanco

{"title":"Nuclear respiratory factor-1 (NRF1) induction as a powerful strategy to deter mitochondrial dysfunction and senescence in mesenchymal stem cells","authors":"Hyunho Lee, Matteo Massaro, Nourhan Abdelfattah, Gherardo Baudo, Haoran Liu, Kyuson Yun, Elvin Blanco","doi":"10.1111/acel.14446","DOIUrl":"10.1111/acel.14446","url":null,"abstract":"Mesenchymal stem cells (MSCs) are promising candidates for regenerative therapies due to their self-renewal and differentiation capabilities. Pathological microenvironments expose MSCs to senescence-inducing factors such as reactive oxygen species (ROS), resulting in MSC functional decline and loss of stemness. Oxidative stress leads to mitochondrial dysfunction, a hallmark of senescence, and is prevalent in aging tissues characterized by elevated ROS levels. We hypothesized that overexpression of nuclear respiratory factor-1 (NRF1), a driver of mitochondrial biogenesis, could metabolically potentiate MSCs and prevent MSC senescence. Single-cell RNA sequencing (scRNA-Seq) revealed that MSCs transfected with NRF1 messenger RNA (mRNA) exhibited upregulated expression of genes associated with oxidative phosphorylation (OXPHOS), decreased glycolytic markers, and suppression of senescence-related pathways. To test whether NRF1 induction could mitigate stress-induced premature senescence, we exposed MSCs to hydrogen peroxide (H2O2) and validated our findings in a replicative senescence model. NRF1 mRNA transfection significantly increased mitochondrial mass and improved aberrant mitochondrial processes associated with senescence, including reduced mitochondrial and intracellular total ROS production. Mitochondrial health and dynamics were preserved, and respiratory function was restored, as evidenced by enhanced OXPHOS, reduced glycolysis, and increased ATP production. Notably, NRF1 overexpression led to decreased senescence-associated β-galactosidase (SA-β-gal) activity and reduced expression of senescence markers p53, p21, and p16. Our findings demonstrate that NRF1 induction attenuates MSC senescence by enhancing mitochondrial function, suggesting potential translational applications for MSC-based therapies and senescence-targeted interventions.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 4","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14446","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DNMT3a Deficiency Contributes to Anesthesia/Surgery-Induced Synaptic Dysfunction and Cognitive Impairment in Aged Mice DNMT3a缺乏与老年小鼠麻醉/手术诱导的突触功能障碍和认知障碍有关

IF 7.8 1区医学

Aging Cell Pub Date : 2024-12-25 DOI: 10.1111/acel.14458

Peilin Cong, Xinwei Huang, Qian Zhang, Mengfan He, Hanxi Wan, Qianqian Wu, Huanghui Wu, Yuxin Zhang, Chun Cheng, Li Tian, Lize Xiong

{"title":"DNMT3a Deficiency Contributes to Anesthesia/Surgery-Induced Synaptic Dysfunction and Cognitive Impairment in Aged Mice","authors":"Peilin Cong, Xinwei Huang, Qian Zhang, Mengfan He, Hanxi Wan, Qianqian Wu, Huanghui Wu, Yuxin Zhang, Chun Cheng, Li Tian, Lize Xiong","doi":"10.1111/acel.14458","DOIUrl":"10.1111/acel.14458","url":null,"abstract":"Perioperative neurocognitive disorder (PND) is a severe postoperative complication in older patients. Epigenetic changes are hallmarks of senescence and are closely associated with cognitive impairment. However, the effects of anesthesia and surgery on the aging brain's epigenetic regulatory mechanisms and its impact on cognitive impairment remain unclear. Using a laparotomy PND model, we report significant reduction in DNA methyltransferase 3a (DNMT3a) in hippocampal neurons of aged mice, which causes global DNA methylation decrease. Knockdown of DNMT3a leads to synaptic disorder and memory impairment in aged mice. Mechanistically, bisulfite sequencing revealed that DNMT3a deficiency reduces methylation in the LRG1 promoter region and promotes its transcription. We also show that activation of TGF-β signaling by the increase in LRG1 level, ultimately impacts the synaptic function. In contrast, both overexpressing DNMT3a or knockdown LRG1 in hippocampus can attenuate the synaptic disorders and rescue postoperative cognitive deficits in aged mice. Our results reveal that DNMT3a is a previously undefined mediator in the pathogenesis of PND, which couples epigenetic regulations with anesthesia/surgery-induced synaptic dysfunction and represents a therapeutic target to tackle PND.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 4","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14458","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype 利用机器学习对脑脊液的蛋白质组分析显示了与APOE4基因型相关的独特蛋白质特征。

IF 7.8 1区医学

Aging Cell Pub Date : 2024-12-25 DOI: 10.1111/acel.14439

Artur Shvetcov, Shannon Thomson, Ann-Na Cho, Heather M. Wilkins, Joanne H. Reed, Russell H. Swerdlow, David A. Brown, the Alzheimer's Disease Neuroimaging Initiative, Caitlin A. Finney

{"title":"Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype","authors":"Artur Shvetcov, Shannon Thomson, Ann-Na Cho, Heather M. Wilkins, Joanne H. Reed, Russell H. Swerdlow, David A. Brown, the Alzheimer's Disease Neuroimaging Initiative, Caitlin A. Finney","doi":"10.1111/acel.14439","DOIUrl":"10.1111/acel.14439","url":null,"abstract":"Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment. Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning. We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased the risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers' vulnerability to cognitive decline and AD as they age.","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 4","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14439","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0