Aging Cell最新文献

{"title":"Single-cell RNA sequencing reveals the CRTAC1⁺ population actively contributes to the pathogenesis of spinal ligament degeneration by SPP1⁺ macrophage.","authors":"Yulong Tang, Dachun Zhuo, Yuexin Yu, Weilin Pu, Yanyun Ma, Yuting Zhang, Yan Huang, Qing Zhang, Kunhai Tang, Chen Meng, Di Yang, Lu Bai, Dongyi He, Li Jin, Hejian Zou, Huji Xu, Qi Zhu, Jiucun Wang, Yuanyuan Chen, Jing Liu","doi":"10.1111/acel.14320","DOIUrl":"https://doi.org/10.1111/acel.14320","url":null,"abstract":"<p><p>Degenerative spinal stenosis is a chronic disease that affects the spinal ligaments and associated bones, resulting in back pain and disorders of the limbs among the elderly population. There are few preventive strategies for such ligament degeneration. We here aimed to establish a comprehensive transcriptomic atlas of ligament tissues to identify high-priority targets for pharmaceutical treatment of ligament degeneration. Here, single-cell RNA sequencing was performed on six degenerative ligaments and three traumatic ligaments to understand tissue heterogeneity. After stringent quality control, high-quality data were obtained from 32,014 cells. Distinct cell clusters comprising stromal and immune cells were identified in ligament tissues. Among them, we noted that collagen degradation associated with CTHRC1⁺ fibroblast-like cells and calcification linked to CRTAC1⁺ chondrocyte-like cells were key features of ligament degeneration. SCENIC analysis and further experiments identified ATF3 as a key transcription factor regulating the pathogenesis of CRTAC1⁺ chondrocyte-like cells. Typically, immune cells infiltrate localized organs, causing tissue damage. In our study, myeloid cells were found to be inflammatory-activated, and SPP1⁺ macrophages were notably enriched in degenerative ligaments. Further exploration via CellChat analysis demonstrated a robust interaction between SPP1⁺ macrophages and CRTAC1⁺ chondrocyte-like cells. Activated by SPP1, ATF3 propels the CRTAC1/MGP/CLU axis, fostering ligament calcification. Our unique resource provides novel insights into possible mechanisms underlying ligament degeneration, the target cell types, and molecules that are expected to mitigate degenerative spinal ligament. We also highlight the role of immune regulation in ligament degeneration and calcification, enhancing our understanding of this disease.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benefit delayed immunosenescence by regulating CD4⁺T cells: A promising therapeutic target for aging-related diseases.","authors":"Tingting Xia, Ying Zhou, Jiayao An, Zhi Cui, Xinqin Zhong, Tianyi Cui, Bin Lv, Xin Zhao, Xiumei Gao","doi":"10.1111/acel.14317","DOIUrl":"https://doi.org/10.1111/acel.14317","url":null,"abstract":"<p><p>CD4⁺T cells play a notable role in immune protection at different stages of life. During aging, the interaction between the body's internal and external environment and CD4⁺T cells results in a series of changes in the CD4⁺T cells pool making it involved in immunosenescence. Many studies have extensively examined the subsets and functionality of CD4⁺T cells within the immune system, highlighted their pivotal role in disease pathogenesis, progression, and therapeutic interventions. However, the underlying mechanism of CD4⁺T cells senescence and its intricate association with diseases remains to be elucidated and comprehensively understood. By summarizing the immunosenescent progress and network of CD4⁺T cell subsets, we reveal the crucial role of CD4⁺T cells in the occurrence and development of age-related diseases. Furthermore, we provide new insights and theoretical foundations for diseases targeting CD4⁺T cell subsets aging as a treatment focus, offering novel approaches for therapy, especially in infections, cancers, autoimmune diseases, and other diseases in the elderly.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cooperative nuclear action of RNA-binding proteins PSF and G3BP2 to sustain neuronal cell viability is decreased in aging and dementia.","authors":"Ken-Ichi Takayama, Takashi Suzuki, Kaoru Sato, Yuko Saito, Satoshi Inoue","doi":"10.1111/acel.14316","DOIUrl":"https://doi.org/10.1111/acel.14316","url":null,"abstract":"<p><p>Dysfunctional RNA-binding proteins (RBPs) have been implicated in several geriatric diseases, including Alzheimer's disease (AD). However, little is known about the nuclear molecular actions and cooperative functions mediated by RBPs that affect gene regulation in sporadic AD or aging. In the present study, we investigated aging- and AD-associated changes in the expression of PSF and G3BP2, which are representative RBPs associated with sex hormone activity. We determined that both PSF and G3BP2 levels were decreased in aged brains compared to young brains of mice. RNA sequencing (RNA-seq) analysis of human neuronal cells has shown that PSF is responsible for neuron-specific functions and sustains cell viability. In addition, we showed that PSF interacted with G3BP2 in the nucleus and stress granules (SGs) at the protein level. Moreover, PSF-mediated gene regulation at the RNA level correlated with G3BP2. Interestingly, PSF and G3BP2 target genes are associated with AD development. Mechanistically, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis demonstrated that the interaction of RBPs with the pre-mRNA of target genes enhanced post-transcriptional mRNA stability, suggesting a possible role for these RBPs in preserving neuronal cell viability. Notably, in the brains of patients with sporadic AD, decreased expression of PSF and G3BP2 in neurons was observed compared to non-AD patients. Overall, our findings suggest that the cooperative action of PSF and G3BP2 in the nucleus is important for preventing aging and AD development.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of the Ca_v1.3 channel in inner hair cells by interleukin 6-dependent inflammaging contributes to age-related hearing loss.","authors":"Mingshun Lu, Fuyu Xian, Xishuo Jin, Guodong Hong, Xiaolong Fu, Shengnan Wang, Xinyu Li, Haichao Yang, Hongchen Li, Haiwei Zhang, Yuxin Yang, Jundan Xiao, Hui Dong, Yaling Liu, Haitao Shen, Ping Lv","doi":"10.1111/acel.14305","DOIUrl":"https://doi.org/10.1111/acel.14305","url":null,"abstract":"<p><p>Age-related hearing loss (AHL) is the most common sensory disorder amongst the older population. Inflammaging is a ≈chronic low-grade inflammation that worsens with age and is an early sign of AHL; however, the underlying mechanisms remain unclear. We used electrophysiological and genetic approaches to establish the importance of interleukin 6 (IL-6)-dependent inflammation in AHL. Elevated IL-6 in the cochlea enhanced Ca_v1.3 calcium channel function in the inner hair cell (IHC) synapse in mice with AHL. IL-6 upregulated the Ca_v1.3 channel via the Janus kinase-mitogen activated kinase pathway, causing neurotransmitter excitotoxicity and synapse impairment; IL-6 deficiency or the administration of a Ca_v1.3 channel blocker attenuated this age-related damage, and rescued hearing loss. Thus, IL-6-dependent inflammaging upregulated the Ca_v1.3 channel in IHCs, contributing to AHL. Our findings could help the comprehensive understanding of inflammaging's effects on AHL, aiding in early intervention to protect against hearing decline.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The connection between aging, cellular senescence and gut microbiome alterations: A comprehensive review.","authors":"Dong-Hyun Jang, Ji-Won Shin, Eunha Shim, Naoko Ohtani, Ok Hee Jeon","doi":"10.1111/acel.14315","DOIUrl":"https://doi.org/10.1111/acel.14315","url":null,"abstract":"<p><p>The intricate interplay between cellular senescence and alterations in the gut microbiome emerges as a pivotal axis in the aging process, increasingly recognized for its contribution to systemic inflammation, physiological decline, and predisposition to age-associated diseases. Cellular senescence, characterized by a cessation of cell division in response to various stressors, induces morphological and functional changes within tissues. The complexity and heterogeneity of senescent cells, alongside the secretion of senescence-associated secretory phenotype, exacerbate the aging process through pro-inflammatory pathways and influence the microenvironment and immune system. Concurrently, aging-associated changes in gut microbiome diversity and composition contribute to dysbiosis, further exacerbating systemic inflammation and undermining the integrity of various bodily functions. This review encapsulates the burgeoning research on the reciprocal relationship between cellular senescence and gut dysbiosis, highlighting their collective impact on age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and osteoarthritis. It also explores the potential of modulating the gut microbiome and targeting cellular senescence as innovative strategies for healthy aging and mitigating the progression of aging-related conditions. By exploring targeted interventions, including the development of senotherapeutic drugs and probiotic therapies, this review aims to shed light on novel therapeutic avenues. These strategies leverage the connection between cellular senescence and gut microbiome alterations to advance aging research and development of interventions aimed at extending health span and improving the quality of life in the older population.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging human abdominal subcutaneous white adipose tissue at single cell resolution.","authors":"K L Whytock, A Divoux, Y Sun, M F Pino, G Yu, C A Jin, J J Robino, A Plekhanov, O Varlamov, S R Smith, M J Walsh, L M Sparks","doi":"10.1111/acel.14287","DOIUrl":"10.1111/acel.14287","url":null,"abstract":"<p><p>White adipose tissue (WAT) is a robust energy storage and endocrine organ critical for maintaining metabolic health as we age. Our aim was to identify cell-specific transcriptional aberrations that occur in WAT with aging. We leveraged full-length snRNA-Seq and histology to characterize the cellular landscape of human abdominal subcutaneous WAT in a prospective cohort of 10 younger (≤30 years) and 10 older individuals (≥65 years) balanced for sex and body mass index (BMI). The older group had greater cholesterol, very-low-density lipoprotein, triglycerides, thyroid stimulating hormone, and aspartate transaminase compared to the younger group (p < 0.05). We highlight that aging WAT is associated with adipocyte hypertrophy, increased proportions of lipid-associated macrophages and mast cells, an upregulation of immune responses linked to fibrosis in pre-adipocyte, adipocyte, and vascular populations, and highlight CXCL14 as a biomarker of these processes. We show that older WAT has elevated levels of senescence marker p16 in adipocytes and identify the adipocyte subpopulation driving this senescence profile. We confirm that these transcriptional and phenotypical changes occur without overt fibrosis and in older individuals that have comparable WAT insulin sensitivity to the younger individuals.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of choline metabolism and therapeutic potential of citicoline in Huntington's disease.","authors":"Kuo-Hsuan Chang, Mei-Ling Cheng, Hsiang-Yu Tang, Chung-Yin Lin, Chiung-Mei Chen","doi":"10.1111/acel.14302","DOIUrl":"https://doi.org/10.1111/acel.14302","url":null,"abstract":"<p><p>Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti-apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of immune cell identity with age inferred from large atlases of single cell transcriptomes.","authors":"Erin Connolly, Tony Pan, Maneesha Aluru, Sriram Chockalingam, Vishal Dhere, Greg Gibson","doi":"10.1111/acel.14306","DOIUrl":"https://doi.org/10.1111/acel.14306","url":null,"abstract":"<p><p>By analyzing two large atlases of almost 4 million cells, we show that immune-senescence involves a gradual loss of cellular identity, reflecting increased cellular heterogeneity, for effector, and cytotoxic immune cells. The effects are largely similar in both males and females and were robustly reproduced in two atlases, one assembled from 35 diverse studies including 678 adults, the other the OneK1K study of 982 adults. Since the mean transcriptional differences among cell-types remain constant across age deciles, there is little evidence for the alternative mechanism of convergence of cell-type identity. Key pathways promoting activation and stemness are down-regulated in aged T cells, while CD8 TEM and CD4 CTLs exhibited elevated inflammatory, and cytotoxicity in older individuals. Elevated inflammatory signaling pathways, such as MAPK and TNF-alpha signaling via NF-kB, also occur across all aged immune cells, particularly amongst effector immune cells. This finding of lost transcriptional identity with age carries several implications, spanning from a fundamental biological understanding of aging mechanisms to clinical perspectives on the efficacy of immunomodulation in elderly people.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of senescent cell subpopulations by CITE-seq analysis.","authors":"Kotb Abdelmohsen, Krystyna Mazan-Mamczarz, Rachel Munk, Dimitrios Tsitsipatis, Qiong Meng, Martina Rossi, Apala Pal, Chang Hoon Shin, Jennifer L Martindale, Yulan Piao, Jinshui Fan, Hagai Yanai, Supriyo De, Isabel Beerman, Myriam Gorospe","doi":"10.1111/acel.14297","DOIUrl":"https://doi.org/10.1111/acel.14297","url":null,"abstract":"<p><p>Cellular senescence, a state of persistent growth arrest, is closely associated with aging and age-related diseases. Deciphering the heterogeneity within senescent cell populations and identifying therapeutic targets are paramount for mitigating senescence-associated pathologies. In this study, proteins on the surface of cells rendered senescent by replicative exhaustion and by exposure to ionizing radiation (IR) were identified using mass spectrometry analysis, and a subset of them was further studied using single-cell CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) analysis. Based on the presence of proteins on the cell surface, we identified two distinct IR-induced senescent cell populations: one characterized by high levels of CD109 and CD112 (cluster 3), the other characterized by high levels of CD112, CD26, CD73, HLA-ABC, CD54, CD49A, and CD44 (cluster 0). We further found that cluster 0 represented proliferating and senescent cells in the G1 phase of the division cycle, and CITE-seq detection of cell surface proteins selectively discerned those in the senescence group. Our study highlights the heterogeneity of senescent cells and underscores the value of cell surface proteins as tools for distinguishing senescent cell programs and subclasses, paving the way for targeted therapeutic strategies in disorders exacerbated by senescence.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unique tau- and synuclein-dependent metabolic reprogramming in neurons distinct from normal aging.","authors":"Shweta Yadav, Aidan Graham, Farazdaq Al Hammood, Chris Garbark, Deepika Vasudevan, Udai Pandey, John M Asara, Dhivyaa Rajasundaram, Andrey A Parkhitko","doi":"10.1111/acel.14277","DOIUrl":"https://doi.org/10.1111/acel.14277","url":null,"abstract":"<p><p>Neuronal cells are highly specialized cells and have a specific metabolic profile to support their function. It has been demonstrated that the metabolic profiles of different cells/tissues undergo significant reprogramming with advancing age, which has often been considered a contributing factor towards aging-related diseases including Alzheimer's (AD) and Parkinson's (PD) diseases. However, it is unclear if the metabolic changes associated with normal aging predispose neurons to disease conditions or a distinct set of metabolic alterations happen in neurons in AD or PD which might contribute to disease pathologies. To decipher the changes in neuronal metabolism with age, in AD, or in PD, we performed high-throughput steady-state metabolite profiling on heads in wildtype Drosophila and in Drosophila models relevant to AD and PD. Intriguingly, we found that the spectrum of affected metabolic pathways is dramatically different between normal aging, Tau, or Synuclein overexpressing neurons. Genetic targeting of the purine and glutamate metabolism pathways, which were dysregulated in both old age and disease conditions partially rescued the neurodegenerative phenotype associated with the overexpression of wildtype and mutant tau. Our findings support a \"two-hit model\" to explain the pathological manifestations associated with AD where both aging- and Tau/Synuclein- driven metabolic reprogramming events cooperate with each other, and targeting both could be a potent therapeutic strategy.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}