IF 8 1区医学

Aging Cell Pub Date : 2025-02-23 DOI: 10.1111/acel.70021

Weifeng Qin, Kathrina D Castillo, Hongye Li, Thi Kim Cuc Nguyen, Daniel L Kiss, John P Cooke, Anahita Mojiri

{"title":"Circular RNA Telomerase Reverses Endothelial Senescence in Progeria.","authors":"Weifeng Qin, Kathrina D Castillo, Hongye Li, Thi Kim Cuc Nguyen, Daniel L Kiss, John P Cooke, Anahita Mojiri","doi":"10.1111/acel.70021","DOIUrl":"https://doi.org/10.1111/acel.70021","url":null,"abstract":"Telomeres shorten with each cell division, acting as a chronometer of cell age. The enzyme telomerase, primarily active in stem cells, reverses telomere erosion. We have previously observed that transient transfection with human TERT mRNA extends telomeres and mitigates hallmarks of senescence in replicatively aged human cells or those affected by Hutchinson-Gilford progeroid syndrome (HGPS). However, due to its short half-life, mRNA requires frequent administration. In this study, we hypothesized that TERT circular (circ) RNA would extend the duration of telomerase expression and be more effective at reversing hallmarks of senescence in endothelial cells derived from HGPS patients. We observe that a single transfection of TERT circRNA is more effective than mRNA in the extension of telomere length, as determined by quantitative fluorescence in situ hybridization. Furthermore, TERT circRNA reduced the number of β-gal positive cells by three-fold and normalized nuclear morphology in HGPS endothelial cells (HGPS-ECs). Moreover, TERT circRNA substantially reduced senescent markers, inflammatory markers, and DNA damage markers, including Progerin, p16, p21, IL-1B, IL-6, IL-8, MCP1, and γH2AX. Additionally, it restored NO production, enhanced cell proliferation, promoted angiogenesis, improved LDL uptake, reduced mitochondrial ROS, and normalized mitochondrial membrane potential more effectively. Our data suggest that TERT circRNA is superior to linear TERT mRNA in reversing processes involved in senescence.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70021"},"PeriodicalIF":8.0,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481794","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}

引用次数: 0

Age-Dependent Clonal Expansion of Non-Sperm-Forming Spermatogonial Stem Cells in Mouse Testes.

IF 8 1区医学

Aging Cell Pub Date : 2025-02-22 DOI: 10.1111/acel.70019

Terumichi Kawahara, Shinnosuke Suzuki, Toshinori Nakagawa, Yuki Kamo, Miki Kanouchi, Miyako Fujita, Maki Hattori, Atsuko Suzuki, Kentaro Tanemura, Shosei Yoshida, Kenshiro Hara

{"title":"Age-Dependent Clonal Expansion of Non-Sperm-Forming Spermatogonial Stem Cells in Mouse Testes.","authors":"Terumichi Kawahara, Shinnosuke Suzuki, Toshinori Nakagawa, Yuki Kamo, Miki Kanouchi, Miyako Fujita, Maki Hattori, Atsuko Suzuki, Kentaro Tanemura, Shosei Yoshida, Kenshiro Hara","doi":"10.1111/acel.70019","DOIUrl":"https://doi.org/10.1111/acel.70019","url":null,"abstract":"In male mammals, spermatogonial stem cells (SSCs) are essential for sustaining lifelong spermatogenesis within the testicular open niche, a unique environment that allows SSC migration over an extended niche area. As SSCs undergo continuous mitotic division, mutations accumulate and are transmitted to the descendant SSC clones. Therefore, SSC clonal fate behaviors, in terms of their efficiencies in completing spermatogenesis and undergoing expansion within the niche, influence sperm genomic diversity. We aimed to elucidate the effects of physiological aging on SSC clonal fate behavior within the testicular open niche. We used single-cell RNA sequencing, lineage tracing, and intravital live imaging to investigate SSC behavior in aged mouse testes, where spermatogenesis, although reduced, persists. We found that undifferentiated spermatogonia maintained gene expression heterogeneity during aging. Among these, GFRα1+ cells, which exhibited state heterogeneity, showed accelerated proliferation and persistent motility, continuing to function as SSCs in older mice. In contrast, a subset of SSCs characterized by low Egr4 and Cops5 expression did not contribute to spermatid formation. These non-sperm-forming SSC clones increased in proportion among the total SSC clones and expanded spatially within the testicular open niche in old mice, a phenomenon not observed in young mice. The expansion of non-sperm-forming SSC clones in aged testes suggests that they occupy a niche space, limiting the availability of functional SSCs and potentially reducing sperm production and genetic diversity. These findings highlight age-specific clonal characteristics as hallmarks of stem cell aging within the testicular open niche and provide novel insights into the mechanisms governing reproductive aging.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70019"},"PeriodicalIF":8.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476160","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}

引用次数: 0

Large-Scale Clustered Transcriptional Silencing Associated With Cellular Senescence.

IF 8 1区医学

Aging Cell Pub Date : 2025-02-19 DOI: 10.1111/acel.70015

Aditi U Gurkar, Satoshi Okawa, Christelle Guillermier, Kritika Chaddha, Matthew L Steinhauser

引用次数: 0

Activated mTOR Signaling in the RPE Drives EMT, Autophagy, and Metabolic Disruption, Resulting in AMD-Like Pathology in Mice.

IF 8 1区医学

Aging Cell Pub Date : 2025-02-17 DOI: 10.1111/acel.70018

Olivia Chowdhury, Sridhar Bammidi, Pooja Gautam, Vishnu Suresh Babu, Haitao Liu, Peng Shang, Ying Xin, Emma Mahally, Mihir Nemani, Victoria Koontz, Kira Lathrop, Katarzyna M Kedziora, Jonathan Franks, Ming Sun, Joshua W Smith, Lauren R DeVine, Robert N Cole, Nadezda Stepicheva, Anastasia Strizhakova, Sreya Chattopadhyay, Stacey Hose, Jacob Samuel Zigler, José-Alain Sahel, Jiang Qian, Prasun Guha, James T Handa, Sayan Ghosh, Debasish Sinha

{"title":"Activated mTOR Signaling in the RPE Drives EMT, Autophagy, and Metabolic Disruption, Resulting in AMD-Like Pathology in Mice.","authors":"Olivia Chowdhury, Sridhar Bammidi, Pooja Gautam, Vishnu Suresh Babu, Haitao Liu, Peng Shang, Ying Xin, Emma Mahally, Mihir Nemani, Victoria Koontz, Kira Lathrop, Katarzyna M Kedziora, Jonathan Franks, Ming Sun, Joshua W Smith, Lauren R DeVine, Robert N Cole, Nadezda Stepicheva, Anastasia Strizhakova, Sreya Chattopadhyay, Stacey Hose, Jacob Samuel Zigler, José-Alain Sahel, Jiang Qian, Prasun Guha, James T Handa, Sayan Ghosh, Debasish Sinha","doi":"10.1111/acel.70018","DOIUrl":"https://doi.org/10.1111/acel.70018","url":null,"abstract":"The mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are crucial for various physiological functions. Although the role of mTORC1 in retinal pigmented epithelium (RPE) homeostasis and age-related macular degeneration (AMD) pathogenesis is established, the function of mTORC2 remains unclear. We investigated both complexes in RPE health and disease. Therefore, in this study, we have attempted to demonstrate that the specific overexpression of mammalian lethal with Sec13 protein 8 (mLST8) in the mouse RPE activates both mTORC1 and mTORC2, inducing epithelial-mesenchymal transition (EMT)-like changes and subretinal/RPE deposits resembling early AMD-like pathogenesis. Aging in these mice leads to RPE degeneration, causing retinal damage, impaired debris clearance, and metabolic and mitochondrial dysfunction. Inhibition of mTOR with TORIN1 in vitro or βA3/A1-crystallin in vivo normalized mTORC1/2 activity and restored function, revealing a novel role for the mTOR complexes in regulating RPE function, impacting retinal health and disease.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70018"},"PeriodicalIF":8.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432087","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}

引用次数: 0

The Impact of Toll-Like Receptor 5 on Liver Function in Age-Related Metabolic Disorders.

IF 8 1区医学

Aging Cell Pub Date : 2025-02-17 DOI: 10.1111/acel.70009

Dong-Hyun Kim, Hye Sun Go, Eun Jae Jeon, Thi Quynh Trang Nguyen, Da Yeon Kim, Hansung Park, Hyo-Ji Eom, Sung Young Kim, Sang Chul Park, Kyung A Cho

{"title":"The Impact of Toll-Like Receptor 5 on Liver Function in Age-Related Metabolic Disorders.","authors":"Dong-Hyun Kim, Hye Sun Go, Eun Jae Jeon, Thi Quynh Trang Nguyen, Da Yeon Kim, Hansung Park, Hyo-Ji Eom, Sung Young Kim, Sang Chul Park, Kyung A Cho","doi":"10.1111/acel.70009","DOIUrl":"https://doi.org/10.1111/acel.70009","url":null,"abstract":"Toll-like receptor 5 (TLR5) plays a critical role beyond its traditional function in innate immunity, significantly impacting metabolic regulation and liver health. Previously, we reported that TLR5 activation extends the healthspan and lifespan of aging mice. This study demonstrates that TLR5 deficiency leads to pronounced metabolic abnormalities with age, primarily affecting liver metabolic functions rather than intestinal inflammation. Comprehensive RNA sequencing analysis revealed that TLR5 deficiency induces gene expression changes in liver tissue similar to those caused by the methionine-choline deficient (MCD) diet, particularly affecting lipid metabolism and circadian rhythm-related genes. TLR5 knockout (TLR5 KO) mice displayed an increased propensity for liver fibrosis and lipid accumulation under the MCD diet, exacerbating liver pathology. Both hepatocytes and hepatic stellate cells in TLR5 KO mice were functionally impacted, leading to metabolic dysfunction and fibrosis. These findings suggest that TLR5 could be a significant target for addressing metabolic diseases that arise and worsen with aging. Furthermore, understanding the mechanisms by which TLR5 activation extends healthspan could provide valuable insights into therapeutic strategies for enhancing longevity and managing age-related metabolic disorders.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70009"},"PeriodicalIF":8.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432089","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}

引用次数: 0

Exploring Lymph Node Stroma Ageing: Immune Implications and Future Directions.

IF 8 1区医学

Aging Cell Pub Date : 2025-02-15 DOI: 10.1111/acel.70000

Yu Yang Ng, Andy Tay

{"title":"Exploring Lymph Node Stroma Ageing: Immune Implications and Future Directions.","authors":"Yu Yang Ng, Andy Tay","doi":"10.1111/acel.70000","DOIUrl":"https://doi.org/10.1111/acel.70000","url":null,"abstract":"Ageing is an inevitable biological process that impacts the immune system, leading to immunosenescence and inflammaging, which contribute to increased susceptibility to infections, autoimmune diseases and cancers in individuals over the age of 65. This review focuses on the ageing of lymph node stromal cells (LNSCs), which are crucial for maintaining lymph node (LN) structure and function. Age-related changes in LNs, such as fibrosis and lipomatosis, disrupt the LN architecture and reduce immune cell recruitment and function, impairing immune responses to infections and vaccinations. The review discusses the structural and functional decline of various LNSC subsets, including fibroblastic reticular cells (FRCs), lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), highlighting their roles in immune cell activation and homeostasis. Potential strategies to restore aged LNSC function, such as enhancing LNSC activation during vaccination and using senotherapeutics, are explored. Outstanding questions regarding the mechanisms of LNSC ageing and how ageing of the LN stroma might impact autoimmune disorders are also addressed. This review aims to stimulate further research into the characterisation of aged LNSCs and the development of therapeutic interventions to improve immune function in the older adults.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70000"},"PeriodicalIF":8.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424460","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}

引用次数: 0

Enhanced Microglial Engulfment of Dopaminergic Synapses Induces Parkinson's Disease-Related Executive Dysfunction in an Acute LPC Infusion Targeting the mPFC.

IF 8 1区医学

Aging Cell Pub Date : 2025-02-15 DOI: 10.1111/acel.70003

Yehao Liu, Rui Chen, Chunyan Mu, Junjie Diao, Yurong Guo, Xiaoyu Yao, Shijie Shi, Mengying Wang, Zhi Zhang, Xiaoling Qin, Chuanxi Tang

{"title":"Enhanced Microglial Engulfment of Dopaminergic Synapses Induces Parkinson's Disease-Related Executive Dysfunction in an Acute LPC Infusion Targeting the mPFC.","authors":"Yehao Liu, Rui Chen, Chunyan Mu, Junjie Diao, Yurong Guo, Xiaoyu Yao, Shijie Shi, Mengying Wang, Zhi Zhang, Xiaoling Qin, Chuanxi Tang","doi":"10.1111/acel.70003","DOIUrl":"https://doi.org/10.1111/acel.70003","url":null,"abstract":"The dysfunction of the dopaminergic projection from the ventral tegmental area (VTA) to the medial prefrontal cortex (mPFC) is believed to play a key role in the pathophysiology of Parkinson's disease (PD) accompanied by executive dysfunction (EDF). In this study, we identified an abnormal increase in lysophosphatidylcholine (LPC) levels in PD patients, which closely correlates with the severity of cognitive impairment. LPC disrupts the miR-2885/TDP-43 signaling pathway in microglia, driving dopaminergic presynaptic engulfment. In LPC-exposed mice, microglial activation via miR-2885/TDP-43/p65 signaling led to inflammatory cytokine and complement release, marking dopaminergic synapses for phagocytosis with a \"PS/C1q\" signal. Following the inhibition of LPC-induced microglial activation through chemogenetic methods, we observed a significant reduction in the phagocytosis of dopaminergic synapses, resulting in improved executive function. The miR-2885 disrupted LPC-induced dopaminergic phagocytosis and alleviated EDF. Furthermore, the accumulation of excessive TDP-43 due to the loss of miR-2885 promoted the engulfment of dopaminergic synapses by facilitating the entry of p65 into the nucleus. Inhibiting TDP-43 levels effectively mitigated LPC-induced EDF. Additionally, supplementing dopamine receptor agonists enhanced the excitability of regional glutamatergic neurons, leading to improved executive function. In summary, LPC exposure in the mPFC impairs microglial regulation, leading to dopaminergic synaptic loss and underactivity of glutamatergic neurons. These changes drive the development of executive dysfunction in PD.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70003"},"PeriodicalIF":8.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424453","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}

引用次数: 0

Transcriptional Heterogeneity and Differential Response of Rod Photoreceptor Pathway Uncovered by Single-Cell RNA Sequencing of the Aging Mouse Retina.

IF 8 1区医学

Aging Cell Pub Date : 2025-02-15 DOI: 10.1111/acel.70001

Laura Campello, Matthew J Brooks, Benjamin R Fadl, Hyo Sub Choi, Soumitra Pal, Anand Swaroop

{"title":"Transcriptional Heterogeneity and Differential Response of Rod Photoreceptor Pathway Uncovered by Single-Cell RNA Sequencing of the Aging Mouse Retina.","authors":"Laura Campello, Matthew J Brooks, Benjamin R Fadl, Hyo Sub Choi, Soumitra Pal, Anand Swaroop","doi":"10.1111/acel.70001","DOIUrl":"https://doi.org/10.1111/acel.70001","url":null,"abstract":"Visual function deteriorates throughout the natural course of aging. Age-related structural and functional adaptations are observed in the retina, the light-sensitive neuronal tissue of the eye where visual perception begins. Molecular mechanisms underlying retinal aging are still poorly understood, highlighting the need to identify biomarkers for better prognosis and alleviation of aging-associated vision impairment. Here, we investigate dynamics of transcriptional dysregulation in the retina and identify affected pathways within distinct retinal cell types. Using an optimized protocol for single-cell RNA sequencing of mouse retinas at 3, 12, 18, and 24 months, we detect a progressive increase in the number of differentially expressed genes across all retinal cell types. The extent and direction of expression changes varies, with photoreceptor, bipolar, and Müller cells showing the maximum number of differentially expressed genes at all age groups. Furthermore, our analyses uncover transcriptionally distinct, heterogeneous subpopulations of rod photoreceptors and bipolar cells, distributed across distinct areas of the retina. Our findings provide a plausible molecular explanation for enhanced susceptibility of rod cells to aging and correlate with the observed loss of scotopic sensitivity in elderly individuals.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70001"},"PeriodicalIF":8.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424543","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}

引用次数: 0

Healthy Aging Metabolomic and Proteomic Signatures Across Multiple Physiological Compartments.

IF 8 1区医学

Aging Cell Pub Date : 2025-02-14 DOI: 10.1111/acel.70014

R Moaddel, J Candia, C Ubaida-Mohien, T Tanaka, A Z Moore, M Zhu, G Fantoni, S Church, J D'Agostino, J Fan, N Shehadeh, S De, E Lehrmann, M Kaileh, E Simonsick, R Sen, J M Egan, L Ferrucci

{"title":"Healthy Aging Metabolomic and Proteomic Signatures Across Multiple Physiological Compartments.","authors":"R Moaddel, J Candia, C Ubaida-Mohien, T Tanaka, A Z Moore, M Zhu, G Fantoni, S Church, J D'Agostino, J Fan, N Shehadeh, S De, E Lehrmann, M Kaileh, E Simonsick, R Sen, J M Egan, L Ferrucci","doi":"10.1111/acel.70014","DOIUrl":"https://doi.org/10.1111/acel.70014","url":null,"abstract":"The study of biomarkers in biofluids and tissues expanded our understanding of the biological processes that drive physiological and functional manifestations of aging. However, most of these studies were limited to examining one biological compartment, an approach that fails to recognize that aging pervasively affects the whole body. The simultaneous modeling of hundreds of metabolites and proteins across multiple compartments may provide a more detailed picture of healthy aging and point to differences between chronological and biological aging. Herein, we report proteomic analyses of plasma and urine collected in healthy men and women, age 22-92 years. Using these data, we developed a series of metabolomic and proteomic predictors of chronological age for plasma, urine, and skeletal muscle. We then defined a biological aging score, which measures the departure between an individual's predicted age and the expected predicted age for that individual based on the full cohort. We show that these predictors are significantly and independently related to clinical phenotypes important for aging, such as inflammation, iron deficiency anemia, muscle mass, and renal and hepatic functions. Despite a different set of selected biomarkers in each compartment, the different scores reflect a similar degree of deviation from healthy aging in single individuals, thus allowing identification of subjects with significant accelerated or decelerated biological aging.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70014"},"PeriodicalIF":8.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424478","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}

引用次数: 0

Correction to "Targeting miR-124/ Ferroportin Signaling Ameliorated Neuronal Cell Death Through Inhibiting Apoptosis and Ferroptosis in Aged Intracerebral Hemorrhage Murine Model".

IF 8 1区医学

Aging Cell Pub Date : 2025-02-13 DOI: 10.1111/acel.70006

引用次数: 0

Aging Cell最新文献