Aging Cell最新文献

{"title":"Aging-Related Myocardial Susceptibility Lowers Cardiac Tolerance to Chronic Intermittent Hypoxia Through Dynamin-Related Protein 1-Associated Mitochondrial Vulnerability","authors":"Yinghui Su,&nbsp;Yuyang Miao,&nbsp;Jin Tan,&nbsp;Feng Wang,&nbsp;Qiang Zhang","doi":"10.1111/acel.70684","DOIUrl":"10.1111/acel.70684","url":null,"abstract":"<p>Chronic intermittent hypoxia (CIH), a cardinal pathophysiological feature of obstructive sleep apnea (OSA), repeatedly exposes the heart to hypoxia-reoxygenation stress. The cardiac outcome of CIH, however, may depend on the biological state of the target myocardium. Here, we investigated whether a pre-existing aging-related myocardial susceptibility lowers the tolerance threshold for CIH-induced injury and whether Dynamin-related protein 1 (Drp1) contributes to the enhanced vulnerability of senescence-like cardiomyocytes under CIH. Using G3 Tert-deficient (Tert^−/−) mice and D-galactose (D-gal)-induced senescence-like primary cardiomyocytes, we show that aging-related susceptibility consistently amplifies CIH-induced cardiac injury. In young wild-type mice, 8 weeks CIH induced early cardiac remodeling and senescence-associated myocardial stress without overt systolic decompensation. In Tert^−/− mice, the same CIH exposure shifted the cardiac response further toward maladaptive remodeling. Compared with CIH alone, EF and FS were reduced by an additional 24.6% and 15.8%, respectively. In senescence-like cardiomyocytes, CIH amplified mitochondrial vulnerability, with impaired energy production, elevated mitochondrial oxidative stress, and a fission-biased mitochondrial dynamics marker profile. Drp1 knockdown did not fully reverse this mitochondrial state but restored 55.1% of the CIH + D-gal induced ATP decline and reversed 47.4% of the mitochondrial ROS excess, while attenuating DNA damage response activation and senescence-associated signaling. These findings indicate that aging-related myocardial susceptibility is not a passive contextual factor in CIH-induced injury but a biological state that actively shapes the cardiac response to repeated hypoxia-reoxygenation stress. Drp1-associated mitochondrial dynamics imbalance may represent a functional link between diminished mitochondrial stress tolerance and amplified cardiomyocyte vulnerability.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13507029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816758","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}

{"title":"DHCR24 Alleviates DNA Damage in Senescent Vascular Endothelial Cells via ENKUR/Ca2+ Signaling","authors":"Han Li,&nbsp;Zhen Yang,&nbsp;Wukaiyang Liang,&nbsp;Jie Huang,&nbsp;Tianyi Ji,&nbsp;Hao Nie,&nbsp;Zixin Wan,&nbsp;Yuqi Qiu,&nbsp;Yi Huang,&nbsp;Le Zhang,&nbsp;Cuntai Zhang,&nbsp;Jinhua Yan","doi":"10.1111/acel.70688","DOIUrl":"10.1111/acel.70688","url":null,"abstract":"<p>DNA damage is considered one of the major contributors to aging. DHCR24, a multifunctional enzyme located within the endoplasmic reticulum (ER), is closely related to DNA damage. Our previous study showed that DHCR24 could delay vascular endothelial cells (ECs) senescence. The relationship between DHCR24 and DNA damage during ECs senescence requires further investigation. Here, we demonstrate that aging activates ATM-mediated DNA damage response (DDR) in human umbilical vein endothelial cells (HUVECs) and mouse pulmonary microvascular endothelial cells (PMVECs), and DHCR24 expression is downregulated. Knocking down DHCR24 in young HUVECs induces the activation of ATM-mediated DDR, which has been confirmed in PMVECs of DHCR24 endothelial-specific knockout mice. Consistently, RNAseq indicated that DHCR24 was essential for cell cycle regulation. Further investigations revealed that both replicatively senescent HUVECs and young HUVECs with DHCR24 knockout exhibited ER stress and mitochondrial dysfunction, which might be attributable to calcium overload resulting from DHCR24 deficiency. In this pathological process, the DHCR24-deficiency-induced upregulation of ENKUR markedly exacerbates calcium overload. Conversely, ENKUR knockdown not only alleviates the ER stress and mitochondrial dysfunction caused by DHCR24 inhibition, but also suppresses the ATM-mediated DDR. Moreover, DHCR24 overexpression reduces the elevated ENKUR levels and simultaneously mitigates DOX-induced calcium overload in HUVECs. Collectively, these findings identify DHCR24-ENKUR-dependent Ca²⁺ signaling as a mechanism linking ER-mitochondrial homeostasis to endothelial DNA damage and senescence. Accordingly, restoring DHCR24 function or regulating calcium signal transduction through this pathway may hold therapeutic potential for delaying vascular ECs senescence and preventing age-related diseases.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811609","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}

{"title":"Creb3l1 Overexpression Improves Flexor Tendon Repair in Aged Rats","authors":"Qian Qian Yang,&nbsp;Zhanghao Huang,&nbsp;Yan Xue,&nbsp;Jia Yu Shi,&nbsp;You Lang Zhou","doi":"10.1111/acel.70682","DOIUrl":"10.1111/acel.70682","url":null,"abstract":"<p>Aging increases tendon injury incidence and poor repair outcomes, but age-related differences in tendon mechanical properties and underlying mechanisms remain unclear. We first analyzed data from the Global Burden of Disease (GBD) database to characterize the associations between aging and population-level changes in tendon injury burden. We found the age-standardized incidence rate (ASIR) of tendon injuries caused by mechanical force decreased with advancing age, whereas the age-standardized prevalence rate (ASPR) increased with age, and the years lived with disability (YLDs) due to tendon injuries also showed an increasing trend with age. Guided by these epidemiological observations, we further performed ex vivo biomechanical assessments using aged rat flexor digitorum longus (FDL) tendon injury models to validate age-related mechanical deterioration at the tissue level, revealing significantly compromised mechanical properties in aged female rat tendons. To uncover the molecular drivers underlying such age-dependent mechanical degeneration, we conducted single-cell RNA sequencing of tendon tissues and identified downregulated expression of <i>Col1a1</i> and <i>Sparc</i> in aged tendons. According to the JASPAR website prediction, the transcription factor Creb3l1 could bind to the promoter regions of both <i>Col1a1</i> and <i>Sparc</i> genes simultaneously, and its overexpression promoted their expression. Finally, in vivo Creb3l1 overexpression upregulated the levels of Col1a1 and Sparc proteins and improved the gliding function, healing strength, and elastic modulus of aged tendons, especially in aged male rats. Collectively, this study links population-based epidemiological evidence with preclinical functional and mechanistic validation, providing insights for risk prediction and novel therapeutic targets for age-related tendon injuries.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13500903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808109","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}

{"title":"Metabolic Profiling of Epigenetic Aging and Its Associations With Aging-Related Phenotypes and Modifiable Lifestyle Factors","authors":"Xunying Zhao,&nbsp;Tianpei Ma,&nbsp;Maoyao Xia,&nbsp;Xinyang Dui,&nbsp;Yangdan Zhong,&nbsp;Xin Chen,&nbsp;Yang Qu,&nbsp;Bowen Lei,&nbsp;Qingwen Zhao,&nbsp;Xueyao Wu,&nbsp;Haiyu Yan,&nbsp;Xingyu Zhang,&nbsp;Ke Jiang,&nbsp;Lin Hu,&nbsp;Lu Long,&nbsp;Mengyu Fan,&nbsp;Jiaqiang Liao,&nbsp;Tao Zhang,&nbsp;Xia Jiang,&nbsp;Jiayuan Li,&nbsp;Ben Zhang","doi":"10.1111/acel.70657","DOIUrl":"10.1111/acel.70657","url":null,"abstract":"<p>Epigenetic aging biomarkers are well-established hallmarks of biological aging, yet their metabolic underpinnings remain largely unexplored. Here, we characterized metabolic signatures associated with five epigenetic aging biomarkers (HorvathAge, HannumAge, DNAmPhenoAge, DunedinPACE, and DNAmTL) and examined their clinical relevance and potential determinants in 7162 Chinese older adults from two cohorts (primary and validation). We observed both shared and distinct metabolic associations across epigenetic aging biomarkers. Metabolic signatures of epigenetic aging biomarkers were derived using elastic net regression, showing moderate correlations with the corresponding epigenetic aging biomarkers (<i>r</i> = 0.21–0.36 in internal testing set, <i>p</i> &lt; 0.05), with external replication further validating metabolic signatures of DNAmPhenoAge, DunedinPACE, and DNAmTL (<i>r</i> = 0.18–0.29, <i>p</i> &lt; 0.05). These five metabolic signatures of epigenetic age acceleration (EAA) exhibited 279 significant associations with aging-related phenotypes including higher disease risk, poorer health status, and adverse clinical indicators. Gallstones, chronic kidney disease, and hepatitis, along with renal-, hepatic- and metabolic-related clinical indicators, were consistently associated with multiple metabolic signatures of EAA. Smoking status, alcohol consumption, body mass index (BMI), and physical activity were identified as modifiable lifestyle factors associated with metabolic signatures of EAA, with BMI showing the most consistent associations. Metabolic signatures of DunedinPACE and DNAmPhenoAA exhibited the most extensive associations with aging-related phenotypes and modifiable lifestyle factors in both primary and validation cohorts. These findings provide novel insights into the metabolic correlates of epigenetic aging biomarkers and underscore the potential of metabolomics-informed metrics of epigenetic aging as informative indicators of physiological decline and lifestyle effects.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808095","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}

{"title":"Network Model to Predict Age-Related Transcriptional Reprogramming","authors":"Tyler J. McNeill,&nbsp;Fabrisia Ambrosio,&nbsp;Hirotaka Iijima","doi":"10.1111/acel.70683","DOIUrl":"https://doi.org/10.1111/acel.70683","url":null,"abstract":"<p>Understanding how secreted factors from aged tissue, often referred to as the senescence-associated secretome, reshape cellular phenotypes remains a major challenge due to the complexity of downstream molecular cascades. Here, we present a computational framework for <i>in silico</i> perturbation modeling designed to predict distinct transcriptional responses to age-specific extracellular environmental cues. We exemplify applications of this framework using articular chondrocytes exposed to secretomes derived from infrapatellar fat pads—an integral component of the cartilage microenvironment—excised from the knee joints of young and aged animals. First, we accessed public transcriptomic data of cartilage from healthy and osteoarthritic knee joints and constructed a cartilage-specific co-expression network using topological overlap matrices, which measure network interconnectedness. We then implemented a Random Walk with Restart to simulate the downstream signal propagation of differentially expressed ligands secreted from young and aged infrapatellar fat pads. We benchmarked predicted perturbation signatures against RNA-seq data from aged chondrocytes treated in vitro with either young or aged infrapatellar fat pad-conditioned medium. Our evaluation pipeline included functional enrichment comparison and receiver operating characteristic analysis. These analyses confirmed that simulated perturbations recapitulated chondrocyte signaling pathways modulated by young and aged infrapatellar fat pad secretomes, including primary effects on mitochondrial respiration, a central hallmark of aging. The network paradigm introduced here provides a data-driven strategy to disentangle how complex, age-dependent extracellular environments influence cellular fate. Ultimately, we anticipate that this pipeline can be extended to diverse tissues and age-related diseases to guide the development of interventions that restore youthful cellular phenotypes.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70683","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785202","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}

{"title":"LivAge: An Online Aging Clock for Murine Transcriptomic Age Estimation","authors":"Víctor Celemín-Capaldi,&nbsp;Guillermina Bea,&nbsp;David Roiz-Valle,&nbsp;Alejandro P. Ugalde,&nbsp;Clea Bárcena,&nbsp;Pedro M. Quirós,&nbsp;José M. P. Freije","doi":"10.1111/acel.70677","DOIUrl":"https://doi.org/10.1111/acel.70677","url":null,"abstract":"<p>The increase in life expectancy over the past century has been accompanied by the recognition of age as the primary risk factor for a wide range of pathologies, including cardiovascular and neurodegenerative diseases, as well as cancer. Thus, the development of interventions that slow the underlying biological processes of aging could have beneficial effects on the prevention or progression of these diseases. To evaluate such geroprotective interventions, quantifying biological damage via aging clocks—particularly those based on transcriptomic biomarkers—has become highly relevant, as they provide estimations with strong biological interpretability. However, the limited availability of transcriptomic clocks for murine experimental models has hindered the implementation of these tools in aging research and their use in evaluating interventions that may have geroprotective effects. Here, we have developed an accurate, accessible, and ready-to-use murine transcriptomic clock that provides robust age predictions for healthy mice using hepatic RNA-seq data. Applying the clock to accelerated-aging models revealed an increased transcriptomic age in progeroid syndromes, demonstrating its ability to capture aging-related biological processes. Finally, considering the main interest of these tools, we show that well-established interventions with geroprotective potential, both genetic (Snell Dwarf, Ames Dwarf, and growth hormone receptor-deficient mice) and environmental (caloric, protein, or methionine restriction, as well as rapamycin supplementation in specific contexts), reduce the transcriptomic age estimated by the clock. These findings indicate that the proposed transcriptomic clock could be a valuable tool for studying the biology of aging and for designing and evaluating potential geroprotective interventions.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70677","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784519","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}

{"title":"Piezo1 Activation Rescues Anabolic Response to Mechanical Loading in Aged Bone via Connexin 43 Hemichannels","authors":"Dezhi Zhao,&nbsp;Jiayue Fu,&nbsp;Han Liu,&nbsp;Shuting Liang,&nbsp;Mingming Song,&nbsp;Aining Zhang,&nbsp;Dong-en Wang,&nbsp;Qianjin Guo,&nbsp;You Zhang,&nbsp;Jiawei Wu,&nbsp;Huiyun Xu","doi":"10.1111/acel.70687","DOIUrl":"https://doi.org/10.1111/acel.70687","url":null,"abstract":"<p>Bone mechanosensitivity declines with age, resulting in a reduced anabolic response to mechanical stimulation. Although the mechanosensitive ion channel Piezo1 plays a critical role in bone mechanoresponsiveness, its mechanisms of mechanotransduction in aged bone remain incompletely understood. Here, we report that aged tibiae from 19-month-old male mice exhibit a blunted anabolic response to axial cyclic compressive loading or administration of the Piezo1 agonist Yoda1 alone. However, chemical activation of osteocytic Piezo1 by Yoda1 effectively rescues the anabolic response of aged cortical bone to mechanical loading. Mechanistically, Yoda1-induced Piezo1 activation promotes its co-localization with connexin 43 (Cx43) on the osteocyte membrane in response to mechanical stimulation. This Piezo1-Cx43 interaction enhances Cx43 hemichannel (HC) activity via the PI3K-Akt signaling pathway. Subsequent HC opening facilitates the release of the anabolic factor prostaglandin E₂ (PGE₂) and suppresses the catabolic factor sclerostin (SOST), thereby promoting bone formation and inhibiting bone resorption on the endosteal surface, which ultimately increases cortical bone mass during mechanical loading. Collectively, our findings reveal a mechanism whereby Piezo1 mediates the skeletal anabolic response to mechanical loading in aged bone via Cx43 HCs, offering new perspectives for combating age-related osteoporosis.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70687","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785077","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}

{"title":"hTERT Immortalization Stabilizes Human Umbilical Cord MSCs and Maintains Their Small Extracellular Vesicles With Preserved Immunomodulatory Activity and Primordial Follicle-Activating Capacity","authors":"Yating Chen,&nbsp;Wei Liu,&nbsp;Ying Tian,&nbsp;Xinyu Wang,&nbsp;Haonan Fan,&nbsp;Mingyu Yang,&nbsp;Feiyang Diao,&nbsp;Jing Li","doi":"10.1111/acel.70681","DOIUrl":"https://doi.org/10.1111/acel.70681","url":null,"abstract":"<p>Cellular senescence is a fundamental hallmark of aging and represents a major barrier to the scalable and reproducible application of mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs). Senescent human umbilical cord mesenchymal stromal cells (hUCMSCs) exhibit impaired proliferative capacity, disrupted mitochondrial homeostasis, and altered secretory phenotypes, which may compromise the biological activity and therapeutic reliability of sEVs. Here, we investigated whether overexpression of human telomerase reverse transcriptase (hTERT) attenuates senescence-associated deterioration and stabilizes sEV functional properties. Late-passage hUCMSCs displayed canonical senescence features and mitochondrial dysfunction, all of which were markedly alleviated by hTERT expression. Functionally, sEVs derived from senescent cells exhibited impaired immunomodulatory activity, whereas sEVs from hTERT-expressing cells largely restored this function. Mechanistically, senescence was associated with altered sEV cargo, including enrichment of miR-217-5p, which contributed to diminished immunomodulatory potency, at least in part through modulation of SIRT1-associated inflammatory signaling in recipient macrophages. Proteomic profiling further showed that H11-sEVs retained a young-like protein cargo profile, particularly for proteins associated with immune and inflammatory regulation. In parallel, sEVs from all three groups retained primordial follicle-activating capacity, consistent with the broad retention of PI3K-Akt pathway-related proteins in their proteomic profiles and PI3K-Akt pathway activation in ovarian tissues. In aged female mice, H11-sEVs exhibited young-like ovarian protective activity. Collectively, these findings demonstrate that hTERT uncouples cellular senescence from sEV functional decline, supporting the development of potency-stabilized sEV sources for aging-related and regenerative applications and providing insight into the biological roles of senescent cell-derived sEVs.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70681","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785122","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}

{"title":"Aging Alters Hair Cell Physiological Properties in Mice With Late-Onset Age-Related Hearing Loss","authors":"Piece Yen,&nbsp;Adam J. Carlton,&nbsp;Andrew O'Connor,&nbsp;Niovi Voulgari,&nbsp;Stuart L. Johnson,&nbsp;Jing-Yi Jeng","doi":"10.1111/acel.70679","DOIUrl":"https://doi.org/10.1111/acel.70679","url":null,"abstract":"<p>Mammalian cochlear hair cells convert acoustic stimuli into electrical signals, which are relayed to the central auditory pathway via auditory neurons. Progressive loss of hair cells and their synapses is a characteristic of age-related hearing loss (ARHL), but the underlying mechanisms remain poorly understood. In this study, we tested the hypothesis that hair cell physiological properties change with age in CBA/CaJ mice, a strain known for its slow ARHL progression. We found that hair cell size began to decrease from 10 months of age, well before detectable increase in hearing thresholds from auditory brainstem responses. This structural change was associated with a significant decrease in the size of the basolateral membrane current, in particular that carried by the large conductance calcium-activated potassium (BK) channel currents (<i>I</i>_K,f) in the apical inner hair cells (IHCs). However, the size of the mechanoelectrical transducer (MET) current measured in the IHCs remained unaffected at least up to 22 months of age. Our results provide clear evidence of an early change in the physiological properties of apical IHCs with age, which precedes measurable hearing loss, suggesting that these cellular deficits might define a distinct pathological route in the CBA/CaJ mice.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70679","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785121","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}

{"title":"RICTOR Prevents Decidualization Disorder in Women With Advanced Maternal Age via Regulating FoxO1 Nuclear Export","authors":"Yifeng Lin,&nbsp;Jiwei Sun,&nbsp;Yue Ying,&nbsp;Dan Li,&nbsp;Yuewen Ying,&nbsp;Xilin Shen,&nbsp;Xiao Sun,&nbsp;Dan Zhang,&nbsp;Yiqing Wu,&nbsp;Runju Zhang","doi":"10.1111/acel.70667","DOIUrl":"https://doi.org/10.1111/acel.70667","url":null,"abstract":"<p>Miscarriage and abnormal embryonic development in women of advanced maternal age (AMA) are often associated with impaired decidualization. mTORC2 is an evolutionarily conserved protein kinase. As a core component of mTORC2, RICTOR has been implicated in nutrient sensing and is closely linked to implantation disorders; however, its role in regulating age-related decidualization disorders remains unreported. In this study, we identified pronounced decidualization defects in AMA foster mice, accompanied by a significant reduction in RICTOR in the decidual tissues of AMA women. Uterine-specific genetic deletion of <i>Rictor</i> in mice resulted in pregnancy loss and impaired decidualization. Notably, <i>Rictor</i> knockdown led to attenuated Akt3–FoxO1 signaling and impaired nuclear export of FoxO1. Molecular and histological analyses demonstrated that the specific RICTOR activator MHY1485 effectively rescued decidualization defects in vivo and in vitro. These findings indicate that RICTOR plays an essential role in the aging decidual microenvironment and may serve as a potential biomarker for uterine stromal cell decidualization. Furthermore, therapeutic activation of RICTOR represents a promising strategy to counteract senescent decidual impairment in AMA women and improve pregnancy outcomes.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70667","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784517","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}