Aging Cell最新文献_第7页

Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature. 血管生成素-2 可逆转早衰症血管中的内皮细胞功能障碍。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-18 DOI: 10.1111/acel.14375

Sahar Vakili, Elizabeth K Izydore, Leonhard Losert, Wayne A Cabral, Urraca L Tavarez, Kevin Shores, Huijing Xue, Michael R Erdos, George A Truskey, Francis S Collins, Kan Cao

{"title":"Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature.","authors":"Sahar Vakili, Elizabeth K Izydore, Leonhard Losert, Wayne A Cabral, Urraca L Tavarez, Kevin Shores, Huijing Xue, Michael R Erdos, George A Truskey, Francis S Collins, Kan Cao","doi":"10.1111/acel.14375","DOIUrl":"https://doi.org/10.1111/acel.14375","url":null,"abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder in children caused by a point mutation in the lamin A gene, resulting in a toxic form of lamin A called progerin. Accelerated atherosclerosis leading to heart attack and stroke are the major causes of death in these patients. Endothelial cell (EC) dysfunction contributes to the pathogenesis of HGPS related cardiovascular diseases (CVD). Endothelial cell-cell communications are important in the development of the vasculature, and their disruptions contribute to cardiovascular pathology. However, it is unclear how progerin interferes with such communications that lead to vascular dysfunction. An antibody array screening of healthy and HGPS patient EC secretomes identified Angiopoietin-2 (Ang2) as a down-regulated signaling molecule in HGPS ECs. A similar down-regulation of Ang2 mRNA and protein was detected in the aortas from an HGPS mouse model. Addition of Ang2 to HGPS ECs rescues vasculogenesis, normalizes endothelial cell migration and gene expression, and restores nitric oxide bioavailability through eNOS activation. Furthermore, Ang2 addition reverses unfavorable paracrine effects of HGPS ECs on vascular smooth muscle cells. Lastly, by utilizing adenine base editor (ABE)-corrected HGPS ECs and progerin-expressing HUVECs, we demonstrated a negative correlation between progerin and Ang2 expression. Lastly, our results indicated that Ang2 exerts its beneficial effect in ECs through Tie2 receptor binding, activating an Akt-mediated pathway. Together, these results provide molecular insights into EC dysfunction in HGPS and suggest that Ang2 treatment has potential therapeutic effects in HGPS-related CVD.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14375"},"PeriodicalIF":8.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453913","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

Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes. 两周的运动会改变患有糖尿病前期的老年人的神经细胞外囊泡胰岛素信号蛋白和前BDNF。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-18 DOI: 10.1111/acel.14369

Steven K Malin, Daniel J Battillo, Michal S Beeri, Maja Mustapic, Francheska Delgado-Peraza, Dimitrios Kapogiannis

{"title":"Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes.","authors":"Steven K Malin, Daniel J Battillo, Michal S Beeri, Maja Mustapic, Francheska Delgado-Peraza, Dimitrios Kapogiannis","doi":"10.1111/acel.14369","DOIUrl":"https://doi.org/10.1111/acel.14369","url":null,"abstract":"Adults with prediabetes are at risk for Alzheimer's Disease and Related Dementia (ADRD). While exercise may lower ADRD risk, the exact mechanism is unclear. We tested the hypothesis that short-term exercise would raise neuronal insulin signaling and pro-BDNF in neuronal extracellular vesicles (nEVs) in prediabetes. Twenty-one older adults (18F, 60.0 ± 8.6 yrs.; BMI: 33.5 ± 1.1 kg/m2) with prediabetes (ADA criteria; 75 g OGTT) were randomized to 12 supervised work-matched continuous (n = 13, 70% HRpeak) or interval (n = 8, 90% HRpeak and 50% HRpeak for 3 min each) sessions over 2-wks for 60 min/d. Aerobic fitness (VO2peak) and body weight were assessed. After an overnight fast, whole-body glucose tolerance (total area under the curve, tAUC) and insulin sensitivity (SIis) were determined from a 120 min 75 g OGTT. nEVs were acquired from 0 and 60 min time-points of the OGTT, and levels of insulin signaling proteins (i.e., p-IRS-1, total-/p-Akt, pERK1/2, pJNK1/2, and pp38) and pro-BNDF were measured. OGTT stimulatory effects were calculated from protein differences (i.e., OGTT 60-0 min). Adults were collapsed into a single group as exercise intensity did not affect nEV outcomes. Exercise raised VO2peak (+1.4 ± 2.0 mL/kg/min, p = 0.008) and insulin sensitivity (p = 0.01) as well as decreased weight (-0.4 ± 0.9 kg, p = 0.04) and whole-body glucose tAUC120min (p = 0.02). Training lowered 0-min pro-BDNF (704.1 ± 1019.0 vs. 414.5 ± 533.5, p = 0.04) and increased OGTT-stimulated tAkt (-51.8 ± 147.2 vs. 95 ± 204.5 a.u., p = 0.01), which was paralleled by reduced pAkt/tAkt at 60 min of the OGTT (1.3 ± 0.2 vs. 1.2 ± 0.1 a.u., p = 0.04). Thus, 2 weeks of exercise altered neuronal insulin signaling responses to glucose ingestion and lowered pro-BNDF among adults with prediabetes, thereby potentially lowering ADRD risk.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14369"},"PeriodicalIF":8.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453924","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

Multiple outcomes of the germline p16^INK4a mutation affecting senescence and immunity in human skin. 种系 p16INK4a 基因突变的多种结果影响人类皮肤的衰老和免疫。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-17 DOI: 10.1111/acel.14373

Priya Subramanian, Souraya Sayegh, Phatthamon Laphanuwat, Oliver P Devine, Carlos Henrique Fantecelle, Justyna Sikora, Emma S Chambers, Sophia N Karagiannis, Daniel C O Gomes, Anjana Kulkarni, Malcolm H A Rustin, Katie E Lacy, Arne N Akbar

{"title":"Multiple outcomes of the germline p16INK4a mutation affecting senescence and immunity in human skin.","authors":"Priya Subramanian, Souraya Sayegh, Phatthamon Laphanuwat, Oliver P Devine, Carlos Henrique Fantecelle, Justyna Sikora, Emma S Chambers, Sophia N Karagiannis, Daniel C O Gomes, Anjana Kulkarni, Malcolm H A Rustin, Katie E Lacy, Arne N Akbar","doi":"10.1111/acel.14373","DOIUrl":"https://doi.org/10.1111/acel.14373","url":null,"abstract":"The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16INK4a. Melanocytes within skin biopsies from FMS patients express significantly less p16INK4a but express higher levels of the DNA-damage protein 𝛾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence-related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in vivo.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14373"},"PeriodicalIF":8.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453918","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

Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia. SVBP 功能失常导致的微管蛋白去酪氨酸化改变诱导细胞分裂失败和衰老，是复杂的遗传性痉挛性截瘫的基础。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-16 DOI: 10.1111/acel.14355

Nathalie Launay, Maria Espinosa-Alcantud, Edgard Verdura, Gorka Fernández-Eulate, Jon Ondaro, Pablo Iruzubieta, Maria Marsal, Agatha Schlüter, Montserrat Ruiz, Stephane Fourcade, Agustí Rodríguez-Palmero, Miren Zulaica, Andone Sistiaga, Garazi Labayru, Pablo Loza-Alvarez, Alejandro Vaquero, Adolfo Lopez de Munain, Aurora Pujol

{"title":"Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia.","authors":"Nathalie Launay, Maria Espinosa-Alcantud, Edgard Verdura, Gorka Fernández-Eulate, Jon Ondaro, Pablo Iruzubieta, Maria Marsal, Agatha Schlüter, Montserrat Ruiz, Stephane Fourcade, Agustí Rodríguez-Palmero, Miren Zulaica, Andone Sistiaga, Garazi Labayru, Pablo Loza-Alvarez, Alejandro Vaquero, Adolfo Lopez de Munain, Aurora Pujol","doi":"10.1111/acel.14355","DOIUrl":"https://doi.org/10.1111/acel.14355","url":null,"abstract":"Senescence, marked by permanent cell cycle arrest may contribute to the decline in regenerative potential and neuronal function, thereby promoting neurodegenerative disorders. In this study, we employed whole exome sequencing to identify a previously unreported biallelic missense variant in SVBP (p.Leu49Pro) in six patients from three unrelated families. These affected individuals present with a complex hereditary spastic paraplegia (HSP), peripheral neuropathy, verbal apraxia, and intellectual disability, exhibiting a milder phenotype compared to patients with nonsense SVBP mutations described previously. Consistent with SVBP's primary role as a chaperone necessary for VASH-mediated tubulin detyrosination, both patient fibroblasts with the p.Leu49Pro mutation, and HeLa cells harboring an SVBP knockdown exhibit microtubule dynamic instability and alterations in pericentriolar material (PCM) component trafficking and centrosome cohesion. In patient fibroblasts, structural abnormalities in the centrosome trigger mitotic errors and cellular senescence. Notably, premature senescence characterized by elevated levels of p16INK4, was also observed in patient peripheral blood mononuclear cells (PBMCs). Taken together, our findings underscore the critical role of SVBP in the development and maintenance of the central nervous system, providing novel insights associating cytokinesis failure with cortical motor neuron disease and intellectual disability.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14355"},"PeriodicalIF":8.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453912","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

Hippocampal Nogo66-NgR1 signaling activation restricts postsynaptic assembly in aged mice with postoperative neurocognitive disorders. 海马 Nogo66-NgR1 信号激活限制了术后神经认知障碍老年小鼠的突触后装配。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-16 DOI: 10.1111/acel.14366

Min Jia, Gui-Zhou Li, Jiang Chen, Xiao-Hui Tang, Yan-Yu Zang, Guo-Lin Yang, Yun Stone Shi, Daqing Ma, Mu-Huo Ji, Jian-Jun Yang

{"title":"Hippocampal Nogo66-NgR1 signaling activation restricts postsynaptic assembly in aged mice with postoperative neurocognitive disorders.","authors":"Min Jia, Gui-Zhou Li, Jiang Chen, Xiao-Hui Tang, Yan-Yu Zang, Guo-Lin Yang, Yun Stone Shi, Daqing Ma, Mu-Huo Ji, Jian-Jun Yang","doi":"10.1111/acel.14366","DOIUrl":"https://doi.org/10.1111/acel.14366","url":null,"abstract":"Postoperative neurocognitive disorders (pNCD) are a common neurological complication, especially in elderly following anesthesia and surgery. Yet, the underlying mechanisms of pNCD remain elusive. This study aimed to investigate the molecular mechanisms that compromise synaptic metaplasticity in pNCD development with a focus on the involvement of Nogo-66 receptor 1 (NgR1) in the pathogenesis of pNCD in aged mice. Aged mice subjected to anesthesia and laparotomy surgery exhibited anxiety-like behavior and contextual fear memory impairment. Moreover, the procedure significantly increased NogoA and NgR1 expressions, particularly in the hippocampal CA1 and CA3 regions. This increase led to the depolymerization of F-actin, attributed to the activation of the RhoA-GTPase, resulting in a reduction of dendritic spines and changes in their morphology. Additionally, these changes hindered the efficient postsynaptic delivery of the subunit GluA1 and GluA2 of AMPA receptors (AMPARs), consequently diminishing excitatory neurotransmission in the hippocampus. Importantly, administering the competitive NgR1 antagonist peptide NEP1-40 (Nogo-A extracellular peptide residues 1-40 amino acids of Nogo-66) and Fasudil (a Rho-kinase inhibitor) effectively mitigated synaptic impairments and reversed neurocognitive deficits in aged mice following anesthesia and surgery. Our work indicates that high hippocampal Nogo66-NgR1 signaling disrupts postsynaptic AMPA receptor surface delivery due to F-actin depolymerization in the pathophysiology of pNCD.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14366"},"PeriodicalIF":8.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453915","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

Ketogenic β-hydroxybutyrate regulates β-hydroxybutyrylation of TCA cycle-associated enzymes and attenuates disease-associated pathologies in Alzheimer's mice. 生酮β-羟丁酸调节TCA循环相关酶的β-羟丁酸化，减轻阿尔茨海默氏症小鼠与疾病相关的病理变化。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-16 DOI: 10.1111/acel.14368

Wanhong Han, Bingchang Zhang, Wenpeng Zhao, Wentao Zhao, Jiawei He, Xiansheng Qiu, Liang Zhang, Xiuyan Wang, Yong Wang, Hanwen Lu, Yaya Zhang, Yuanyuan Xie, Yanyan Geng, Wujie Zhao, Qionghui Huang, Yun-Wu Zhang, Zhanxiang Wang

{"title":"Ketogenic β-hydroxybutyrate regulates β-hydroxybutyrylation of TCA cycle-associated enzymes and attenuates disease-associated pathologies in Alzheimer's mice.","authors":"Wanhong Han, Bingchang Zhang, Wenpeng Zhao, Wentao Zhao, Jiawei He, Xiansheng Qiu, Liang Zhang, Xiuyan Wang, Yong Wang, Hanwen Lu, Yaya Zhang, Yuanyuan Xie, Yanyan Geng, Wujie Zhao, Qionghui Huang, Yun-Wu Zhang, Zhanxiang Wang","doi":"10.1111/acel.14368","DOIUrl":"https://doi.org/10.1111/acel.14368","url":null,"abstract":"Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification that has recently been found to regulate protein functions. However, whether and how protein Kbhb modification participates in Alzheimer's disease (AD) remains unknown. Herein, we carried out 4D label-free β-hydroxybutylation quantitative proteomics using brain samples of 8-month-old and 2-month-old APP/PS1 AD model mice and wild-type (WT) controls. We identified a series of tricarboxylic acid (TCA) cycle-associated enzymes including citrate synthase (CS) and succinate-CoA ligase subunit alpha (SUCLG1), whose Kbhb modifications were decreased in APP/PS1 mice at pathological stages. Sodium β-hydroxybutyrate (Na-β-OHB) treatment markedly increased Kbhb modifications of CS and SUCLG1 and their enzymatic activities, leading to elevated ATP production. We further found that Kbhb modifications at lysine 393 site in CS and at lysine 81 site in SUCLG1 were crucial for their enzymatic activities. Finally, we found that β-OHB levels were decreased in the brain of APP/PS1 mice at pathological stages. While ketogenic diet not only significantly increased β-OHB levels, Kbhb modifications and enzymatic activities of CS and SUCLG1, and ATP production, but also dramatically attenuated β-amyloid plaque pathologies and microgliosis in APP/PS1 mice. Together, our findings indicate the importance of protein Kbhb modification for maintaining normal TCA cycle and ATP production and provide a novel molecular mechanism underlying the beneficial effects of ketogenic diet on energy metabolism and AD intervention.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14368"},"PeriodicalIF":8.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453916","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

Aβ -induced excessive mitochondrial fission drives type H blood vessels injury to aggravate bone loss in APP/PS1 mice with Alzheimer's diseases. Aβ诱导的线粒体过度分裂促使H型血管损伤，加剧了阿尔茨海默病APP/PS1小鼠的骨质流失。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-16 DOI: 10.1111/acel.14374

Weidong Zhang, Fan Ding, Xing Rong, Qinghua Ren, Tomoka Hasegawa, Hongrui Liu, Minqi Li

{"title":"Aβ -induced excessive mitochondrial fission drives type H blood vessels injury to aggravate bone loss in APP/PS1 mice with Alzheimer's diseases.","authors":"Weidong Zhang, Fan Ding, Xing Rong, Qinghua Ren, Tomoka Hasegawa, Hongrui Liu, Minqi Li","doi":"10.1111/acel.14374","DOIUrl":"https://doi.org/10.1111/acel.14374","url":null,"abstract":"Alzheimer's diseases (AD) patients suffer from more serious bone loss than cognitively normal subjects at the same age. Type H blood vessels were tightly associated with bone homeostasis. However, few studies have concentrated on bone vascular alteration and its role in AD-related bone loss. In this study, APP/PS1 mice (4- and 8-month-old) and age-matched wild-type mice were used to assess the bone vascular alteration and its role in AD-related bone loss. Transmission electron microscopy, immunofluorescence staining and iGPS 1.0 software database were utilized to investigate the molecular mechanism. Mitochondrial division inhibitor (Mdivi-1) and GSK-3β inhibitor (LiCl) were used to rescue type H blood vessels injury and verify the molecular mechanism. Our results revealed that APP/PS1 mice exhibited more serious bone blood vessels injury and bone loss during ageing. The bone blood vessel injury, especially in type H blood vessels, was accompanied by impaired vascularized osteogenesis in APP/PS1 mice. Further exploration indicated that beta-amyloid (Aβ) promoted the apoptosis of vascular endothelial cells (ECs) and resulted in type H blood vessels injury. Mechanistically, Aβ-induced excessive mitochondrial fission was found to be essential for the apoptosis of ECs. GSK-3β was identified as a key regulatory target of Aβ-induced excessive mitochondrial fission and bone loss. The findings delineated that Aβ-induced excessive mitochondrial fission drives type H blood vessels injury, leading to aggravate bone loss in APP/PS1 mice and GSK-3β inhibitor emerges as a potential therapeutic strategy.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14374"},"PeriodicalIF":8.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453914","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 translation initiation factor eIF2α regulates lipid homeostasis and metabolic aging. 翻译起始因子 eIF2α 调节脂质平衡和代谢衰老。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-15 DOI: 10.1111/acel.14348

Haipeng Huang, Yilie Liao, Ning Li, Xingfan Qu, Chaocan Li, Jiaqi Hou

引用次数: 0

The N6-methyladenosine landscape of ovarian development and aging highlights the regulation by RNA stability and chromatin state. 卵巢发育和衰老的 N6-甲基腺苷图谱突出了 RNA 稳定性和染色质状态的调控作用。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-15 DOI: 10.1111/acel.14376

Xiujuan Hu, Jiafeng Lu, Chenyue Ding, Jincheng Li, Qinyan Zou, Wenjuan Xia, Chunfeng Qian, Hong Li, Boxian Huang

{"title":"The N6-methyladenosine landscape of ovarian development and aging highlights the regulation by RNA stability and chromatin state.","authors":"Xiujuan Hu, Jiafeng Lu, Chenyue Ding, Jincheng Li, Qinyan Zou, Wenjuan Xia, Chunfeng Qian, Hong Li, Boxian Huang","doi":"10.1111/acel.14376","DOIUrl":"https://doi.org/10.1111/acel.14376","url":null,"abstract":"The versatile epigenetic modification known as N6-methyladenosine (m6A) has been demonstrated to be pivotal in numerous physiological and pathological contexts. Nonetheless, the precise regulatory mechanisms linking m6A to histone modifications and the involvement of transposable elements (TEs) in ovarian development and aging are still not completely understood. First, we discovered that m6A modifications are highly expressed during ovarian aging (OA), with significant contributions from decreased m6A demethylase FTO and overexpressed m6A methyltransferase METTL16. Then, using FTO knockout mouse model and KGN cell line, we also observed that FTO deletion and METTL16 overexpression significantly increased m6A levels. This led to the downregulation of the methyltransferase SUV39H1, resulting in reduced H3K9me3 expression. The downregulation of SUV39H1 and H3K9me3 primarily activated LTR7 and LTR12, subsequently activating ERV1. This resulted in a decrease in cell proliferation, while the levels of apoptosis, cellular aging markers, and autophagy markers significantly increased in OA. In summary, our study offers intriguing insights into the role of m6A in regulating DNA epigenetics, including H3K9me3 and TEs, as well as autophagy, thereby accelerating OA.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14376"},"PeriodicalIF":8.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453922","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

Senolytic therapy combining Dasatinib and Quercetin restores the chondrogenic phenotype of human osteoarthritic chondrocytes by the release of pro-anabolic mediators. 结合达沙替尼和槲皮素的衰老疗法通过释放促合成代谢介质恢复了人类骨关节炎软骨细胞的软骨表型。

IF 8 1区医学

Aging Cell Pub Date : 2024-10-14 DOI: 10.1111/acel.14361

Svenja Maurer, Valeria Kirsch, Leonie Ruths, Rolf E Brenner, Jana Riegger

{"title":"Senolytic therapy combining Dasatinib and Quercetin restores the chondrogenic phenotype of human osteoarthritic chondrocytes by the release of pro-anabolic mediators.","authors":"Svenja Maurer, Valeria Kirsch, Leonie Ruths, Rolf E Brenner, Jana Riegger","doi":"10.1111/acel.14361","DOIUrl":"https://doi.org/10.1111/acel.14361","url":null,"abstract":"Cellular senescence is associated with various age-related disorders and is assumed to play a major role in the pathogenesis of osteoarthritis (OA). Based on this, we tested a senolytic combination therapy using Dasatinib (D) and Quercetin (Q) on aged isolated human articular chondrocytes (hACs), as well as in OA-affected cartilage tissue (OARSI grade 1-2). Stimulation with D + Q selectively eliminated senescent cells in both, cartilage explants and isolated hAC. Furthermore, the therapy significantly promoted chondroanabolism, as demonstrated by increased gene expression levels of COL2A1, ACAN, and SOX9, as well as elevated collagen type II and glycosaminoglycan biosynthesis. Additionally, D + Q treatment significantly reduced the release of SASP factors (IL6, CXCL1). RNA sequencing analysis revealed an upregulation of the anabolic factors, inter alia, FGF18, IGF1, and TGFB2, as well as inhibitory effects on cytokines and the YAP-1 signaling pathway, explaining the underlying mechanism of the chondroanabolic promotion upon senolytic treatment. Accordingly, stimulation of untreated hAC with conditioned medium of D + Q-treated cells similarly induced the expression of chondrogenic markers. Detailed analyses demonstrated that chondroanabolic effects could be mainly attributed to Dasatinib, while monotherapeutical application of Quercetin or Navitoclax did not promote the chondroanabolism. Overall, D + Q therapy restored the chondrogenic phenotype in OA hAC most likely by creating a pro-chondroanabolic environment through the reduction of SASP factors and upregulation of growth factors. This senolytic approach could therefore be a promising candidate for further testing as a disease-modifying osteoarthritis drug.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14361"},"PeriodicalIF":8.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453920","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