Aging Cell最新文献

{"title":"Oxygenaging: A Physiological Framework for Geroscience","authors":"Stefano Donega,&nbsp;Kenneth W. Fishbein,&nbsp;Paolo Dominelli,&nbsp;Allison B. Herman,&nbsp;Rafael de Cabo,&nbsp;Myriam Gorospe,&nbsp;Luigi Ferrucci","doi":"10.1111/acel.70664","DOIUrl":"10.1111/acel.70664","url":null,"abstract":"<p>The stepwise movement of oxygen from the atmosphere to the mitochondria, the “oxygen cascade”, is one of the most tightly regulated systems in physiology. Despite decades of mechanistic study, it has remained quite unexplored in Geroscience. This oversight should be reconsidered. In young organisms, hypoxic stress (whether environmental or tissue-specific) activates a complex adaptive response to preserve energetic stability via restraining anabolic pathways, optimizing mitochondrial performance, and reinforcing cellular quality control systems. With advancing age, angiostatic signaling increases, endothelial metabolism becomes dysregulated, and overall alveolar ventilation and pulmonary gas exchange (ventilation–perfusion matching and diffusion capacity) become less efficient. These changes promote microvascular rarefaction and low-grade but persistent mismatches between oxygen delivery and demand at the tissue level, ultimately destabilizing cellular function. In this review, we propose that the gradual erosion of oxygen homeostasis is not simply a byproduct of aging, but also a driver of molecular damage and functional decline. We examine the aging oxygen cascade through the framework of resilience biology, focusing on mechanisms such as mitochondrial electron leaks, oxidative stress amplification, iron dyshomeostasis, ferroptosis, and epigenetic remodeling. We also discuss interventions that alter oxygen availability, such as intermittent hypoxia, hyperbaric oxygen therapy, and hypoxic–hyperoxic training. These approaches demonstrate adaptive potential, but they also highlight the narrow margin between beneficial stress and injury. We propose “Oxygenaging” as a unifying framework in which aging associates with the progressive loss of equilibrium across the oxygen cascade, linking systemic oxygen transport to mitochondrial function, genomic stability, and cellular resilience.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70664","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838570","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":"Shelterin TPP1 Promotes Hair Regeneration Through Activating Bulge Hair Follicle Stem Cells","authors":"Lihui Wang,&nbsp;Bihan Zhao,&nbsp;Jiahui Yang,&nbsp;Ying Liang,&nbsp;Yitian Yao,&nbsp;Xiao Xiao,&nbsp;Long Yang,&nbsp;Jinghao Xia,&nbsp;Haoze Li,&nbsp;Ling Gao,&nbsp;Jun Zhang,&nbsp;Tianci Su,&nbsp;Hao Xu,&nbsp;Jiacheng Zhang,&nbsp;Hongyan Wang,&nbsp;Jun Liu,&nbsp;Xiaojing Hong,&nbsp;Jun-Ping Liu","doi":"10.1111/acel.70692","DOIUrl":"10.1111/acel.70692","url":null,"abstract":"<p>Telomere shortening drives hair follicle senescence, yet successful reversal of this aging process has remained elusive. Here, we report that stem cell overexpression of <i>Acd</i>, the gene encoding TPP1 (telomere protection protein 1)—a shelterin component that recruits telomerase—accelerates hair regeneration in mice. Stabilization of TPP1 protein via topical application of TELODIN, a synthetic octapeptide that inhibits TPP1 degradation, similarly promotes hair regeneration. Mechanistically, increased TPP1 mobilizes bulge hair follicle stem cells (bHFSCs) by coordinating telomere capping and telomerase recruitment. By facilitating the synchronization and transition of hair follicles from the quiescent telogen phase to the proliferative anagen phase, TPP1 drives bHFSCs proliferation, differentiation, and migration. These findings identify TPP1 as a master regulator of hair regeneration through telomere capping and elongation, and suggest that topical TELODIN represents a novel therapeutic strategy for advancing hair growth. This work establishes a therapeutic framework for telomere-targeted interventions against alopecia.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70692","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838617","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":"A Mechanism-Based Framework for Anti-Aging Strategies: From Metabolic Regulation to Senotherapy and Stem Cell-Based Interventions","authors":"Feifei Li,&nbsp;Yankai Wang,&nbsp;Gelin Wang,&nbsp;Jiguo Chen,&nbsp;Song Huang","doi":"10.1111/acel.70658","DOIUrl":"10.1111/acel.70658","url":null,"abstract":"<p>The global prevalence of aging and age-related diseases has increased markedly in recent decades due to extended life expectancy and a growing aging population, posing substantial medical and social burdens. Multiple strategies, including metabolic modulation (e.g., physical exercise, calorie restriction, and calorie restriction mimetics), targeting inflammaging, senotherapy, parabiosis, stem cell-based therapies, and epigenetic rejuvenation, have shown promise in slowing aging and extending lifespan in preclinical models, with some demonstrating efficacy in clinical trials. This review summarizes the current status of leading anti-aging interventions, their clinical progress, and the underlying mechanisms, which include enhancing autophagy, clearing senescent cells and supporting mitochondrial function to reduce chronic inflammation. We propose that metabolic modulation, inflammaging control, and senotherapy constitute three interconnected pillars of contemporary anti-aging strategies.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70658","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838582","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":"Timing-Dependent Clearance of p16-Positive Cells Mitigates Radiation-Induced Accelerated Aging","authors":"Karla Valdivieso,&nbsp;Melanie Weigand,&nbsp;Daniela G. Costa,&nbsp;Gung Lee,&nbsp;Nick Pirius,&nbsp;Helene Martini,&nbsp;Shivangi Oberai,&nbsp;Christina Inman,&nbsp;Yi Zhu,&nbsp;Thomas von Zglinicki,&nbsp;Sundeep Khosla,&nbsp;Nathan LeBrasseur,&nbsp;João F. Passos,&nbsp;Tamara Tchkonia,&nbsp;James L. Kirkland,&nbsp;Diana Jurk","doi":"10.1111/acel.70693","DOIUrl":"10.1111/acel.70693","url":null,"abstract":"<p>Genotoxic stress induced by cancer therapies is increasingly recognized as a driver of accelerated aging in long-term cancer survivors, yet the mechanisms responsible for the emergence of age-related dysfunction months to years after treatment remain poorly understood. Here, we use sublethal whole-body irradiation as a model of systemic genotoxic stress to test whether senescent cells contribute to the progression of post-therapy age-related dysfunction and whether the benefits of senescent cell clearance depend on the timing of intervention. Using the <i>INK-ATTAC</i> mouse model, we selectively eliminated p16^Ink4a-positive cells either early (1 month) or later (4 months) after irradiation. Early clearance had no effect on lifespan or functional outcomes. In contrast, delayed clearance markedly reduced frailty, improved neuromuscular and cognitive function, restored blood–brain barrier integrity, improved hepatic metabolic dysfunction, and increased median survival, with the survival benefit being most evident in female mice. Mechanistically, irradiation induced an early p21^Cip1-associated stress response and later accumulation of p16^Ink4a-positive cells in the brain and liver, which was associated with inflammation and tissue dysfunction. Clearance of p16^Ink4a-positive cells at the later stage attenuated these changes. Together, these findings identify p16^Ink4a-positive cells as key drivers of the radiation-induced accelerated aging-like state that emerges progressively after genotoxic stress. They also show that the efficacy of senescence-targeted interventions depends on when treatment is initiated, with implications for improving long-term outcomes in cancer survivors.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70693","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823825","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":"Associations Between Accelerometer-Assessed Sleep Patterns, Proteomic Signatures, and Hallmarks of Aging in Adulthood","authors":"Ruiyi Liu,&nbsp;Jingsong Luo,&nbsp;Yangchang Zhang,&nbsp;Furong Wang,&nbsp;Jing Xu,&nbsp;Wangnan Cao,&nbsp;Shengzhi Sun","doi":"10.1111/acel.70685","DOIUrl":"10.1111/acel.70685","url":null,"abstract":"<p>The associations between objectively measured sleep patterns, the hallmarks of aging, and their shared proteomic signatures remain poorly understood. In this study, we utilized wrist-worn accelerometer data, plasma proteomic profiles, and health records from the UK Biobank to examine the associations between six defined sleep patterns and nine established hallmarks of aging. We further identified proteins jointly associated with both sleep patterns and aging hallmarks. Longer total sleep duration, greater deep sleep, and increased rapid eye movement (REM) sleep were associated with lower risk of most aging hallmarks. In contrast, higher wakefulness after sleep onset (WASO) and greater sleep irregularity were associated with higher risk, whereas light sleep showed no significant associations. The number of overlapping proteins varied substantially across sleep-hallmark associations, ranging from 1 to 558. These proteins were predominantly enriched in immune and inflammatory pathways. Several proteins, including IL1RN, FABP1, GDF15, and LEP, were consistently observed across multiple sleep patterns and aging hallmarks. These findings may help generate hypotheses about shared underlying biological processes between sleep and the aging process.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 9","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70685","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823800","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-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}