Aging Cell最新文献_第5页

Novel Therapeutic Insights Into Alzheimer's Disease: Glymphatic System and Meningeal Lymphatic Vessels. 阿尔茨海默病的新治疗见解：淋巴系统和脑膜淋巴管。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70699

Bingbing Song, Wei Wang, Siqi Liu, Xi Jin, Yan Qi, Mingquan Li, Dongjie Yue, Yu Liu, Xiangqi Li, Lei Yin, Lina Feng

{"title":"Novel Therapeutic Insights Into Alzheimer's Disease: Glymphatic System and Meningeal Lymphatic Vessels.","authors":"Bingbing Song, Wei Wang, Siqi Liu, Xi Jin, Yan Qi, Mingquan Li, Dongjie Yue, Yu Liu, Xiangqi Li, Lei Yin, Lina Feng","doi":"10.1111/acel.70699","DOIUrl":"10.1111/acel.70699","url":null,"abstract":"With the acceleration of global aging, the relationship between Alzheimer's disease (AD) and the glymphatic system (GS) has become a research hotspot in the field of neuroscience in recent years. Traditionally, the central nervous system was thought to lack a lymphatic system; however, research over the past decade has overturned this view. Studies have revealed the existence of GS and meningeal lymphatic vessels (mLVs) in the brain, which clear metabolic waste (such as amyloid-β and tau proteins) through the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF). Dysfunction of the GS can lead to abnormal deposition of pathological proteins, which may trigger or exacerbate AD. Currently, the association between the GS and AD treatment mainly focuses on drug development (such as small molecules that promote glymphatic circulation), physical therapies (such as 40 Hz photoacoustic therapy), and surgical interventions (primarily deep cervical lymphatic-vein anastomosis and cranial bone maneuver), all of which are under exploration. With the precision of diagnostic technologies and the targeting of therapeutic methods, future intervention strategies surrounding GS may become a significant breakthrough in overcoming the treatment impasse of AD, bringing new hope to tens of millions of AD patients worldwide.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70699"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917681","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}

引用次数: 0

Insights Into the Interplay Between the Senescent Cells and Immune Cells. 对衰老细胞和免疫细胞之间相互作用的见解。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70698

Martin Jaros, Marco Schmidt, Lavinia Neubert, Jan-Christopher Kamp, Sibylle von Vietinghoff, Jan Hinrich Bräsen, Roland Schmitt, Anette Melk

{"title":"Insights Into the Interplay Between the Senescent Cells and Immune Cells.","authors":"Martin Jaros, Marco Schmidt, Lavinia Neubert, Jan-Christopher Kamp, Sibylle von Vietinghoff, Jan Hinrich Bräsen, Roland Schmitt, Anette Melk","doi":"10.1111/acel.70698","DOIUrl":"10.1111/acel.70698","url":null,"abstract":"Aging kidneys exhibit accumulation of senescent cells together with sterile low-grade inflammation. However, the spatial organization of senescence-associated immune cell accumulation in the aging kidney remains poorly defined. We systematically analyzed kidneys from young, middle-aged, and aged mice, focusing on the spatial relationship between senescent tubular cells and distinct immune cell populations. Senescent tubular cells showed significant local enrichment of immune cells, with macrophages representing the most prominent associated immune cell population. This spatial association was more closely linked to p16Ink4a burden as an indicator of biological aging than to chronological age alone, as kidneys with higher p16Ink4a levels displayed enhanced inflammatory and SASP-associated transcriptional signatures. Complementary spatial transcriptomic analyses identified a cortex-restricted senescence-associated neighborhood enriched for inflammatory, macrophage-related, and failed-repair tubular transcriptional programs, supporting the presence of localized senescence-associated inflammatory niches at the transcriptomic level. Both, genetic and pharmacological senolytic interventions reduced senescent-cell burden and decreased immune cell accumulation in aged kidneys. However, macrophages remained preferentially localized near residual senescent tubular structures after senolysis, consistent with persistent local immune senescent cell interactions. Our findings provide quantitative spatial evidence that senescence-associated inflammatory niches emerge in the aging kidney cortex and can be modulated by senolytic intervention. Together, these results establish a spatial framework for renal inflammaging and highlight senescence-associated inflammatory microenvironments as potential therapeutic targets in kidney aging.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70698"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885767","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}

引用次数: 0

In Vivo Base Editing Partially Rescues Bone Dysplasia in a Mouse Model of Hutchinson-Gilford Progeria Syndrome. 体内碱基编辑部分修复了Hutchinson-Gilford早衰综合征小鼠模型的骨发育不良

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70700

Wayne A Cabral, Caleb M Grenko, Diana Yeritsyan, Indeevar Beeram, Shubham Laiwala, Lukas R Johnson, Urraca L Tavarez, Tingfen Yan, Stephen M Wincovitch, Luke W Koblan, Xin D Gao, Meirui An, Narisu Narisu, Leslie G Biesecker, David R Liu, Ara Nazarian, Francis S Collins, Michael R Erdos

{"title":"In Vivo Base Editing Partially Rescues Bone Dysplasia in a Mouse Model of Hutchinson-Gilford Progeria Syndrome.","authors":"Wayne A Cabral, Caleb M Grenko, Diana Yeritsyan, Indeevar Beeram, Shubham Laiwala, Lukas R Johnson, Urraca L Tavarez, Tingfen Yan, Stephen M Wincovitch, Luke W Koblan, Xin D Gao, Meirui An, Narisu Narisu, Leslie G Biesecker, David R Liu, Ara Nazarian, Francis S Collins, Michael R Erdos","doi":"10.1111/acel.70700","DOIUrl":"10.1111/acel.70700","url":null,"abstract":"Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most patients harbor a c.1824C>T/p.G608= variant, commonly described as G608G, in exon 11 of LMNA that leads to aberrant splicing and production of the toxic progerin protein. In addition to cardiovascular, dermal, and adipose tissue deterioration, HGPS mouse models also develop progressive bone dysplasia that occurs in patients. Here we characterize the efficacy of in vivo mutation correction with an adenine base editor (ABE) to rescue structural and functional defects in HGPS transgenic murine bone tissue. Treatment of double-copy transgenic osteoblast cultures with a lentiviral-delivered CRISPR-Cas9 ABE achieved nearly 40% gene correction in vitro, resulting in significant reduction of progerin transcripts and protein, in the absence of selective agents. Furthermore, gene correction improved progeroid osteoblasts' capacity to deposit and mineralize extracellular matrix compared to untreated cultures. In vivo, a single intravenous dose of AAV9-delivered ABE corrected the mutation, achieving ~14%, ~22%, ~10% and < 1% correction in bone by six months of age when administered at P3, P14, 1 and 4 months of age, respectively. Partially rescued bone structural and physical parameters were observed in P14-treated mice with concomitant normalization of gene transcriptional programs and intracellular signaling pathways involved in bone remodeling. This work demonstrates in vivo delivery of a locus-specific DNA base editor to bone tissue, delineates the timing of treatment required for maximum efficacy, and suggests that this system might be tailored for application to other monogenic bone disorders.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70700"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885717","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}

引用次数: 0

Sustained Activation of CaMKII Promotes Skeletal Muscle Contractile Dysfunction in Aging. CaMKII的持续激活促进衰老骨骼肌收缩功能障碍。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70704

Michael R Bene, Tae Chung, Elizabeth D Luczak, Gabriel Lopez-Cecetaite, William A Fountain, Giovanni Rosales-Soto, Erick Hernández-Ochoa, Corina Antonescu, Liliana Florea, Seeun J Jeong, Emily Elassal, Anne Le, Qian-Li Xue, Ahmet Hoke, Peter M Abadir, Qinchuan Wang

{"title":"Sustained Activation of CaMKII Promotes Skeletal Muscle Contractile Dysfunction in Aging.","authors":"Michael R Bene, Tae Chung, Elizabeth D Luczak, Gabriel Lopez-Cecetaite, William A Fountain, Giovanni Rosales-Soto, Erick Hernández-Ochoa, Corina Antonescu, Liliana Florea, Seeun J Jeong, Emily Elassal, Anne Le, Qian-Li Xue, Ahmet Hoke, Peter M Abadir, Qinchuan Wang","doi":"10.1111/acel.70704","DOIUrl":"10.1111/acel.70704","url":null,"abstract":"Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. Exercise engages calcium (Ca2+)- and redox-dependent signaling pathways that enhance muscle performance and adaptation, whereas aging disrupts Ca2+ and redox homeostasis. CaMKII is a key transducer of both signals, raising the possibility that sustained CaMKII signaling becomes maladaptive with aging. Here, we show that CaMKII protein abundance is increased in aged mouse skeletal muscle and that sustained CaMKII activation in young muscle is sufficient to impair contractile function before substantial atrophy develops and, with prolonged activation, to promote progressive muscle loss. Sustained CaMKII activation also disrupted mitochondrial organization and shifted the young-muscle transcriptome toward an aged profile characterized by inflammatory and stress-response pathways. Inhibiting canonical NF-κB signaling partially preserved contractile force during prolonged CaMKII activation without preserving muscle mass, and mediation analysis implicated heme/iron-related transcriptional remodeling in the muscle-mass-independent decline in force. Conversely, expression of CN19o, a peptide inhibitor of CaMKII, in aged muscle improved contractile function and shifted the transcriptome away from an aging-associated profile without inducing hypertrophy. Together, these findings identify sustained CaMKII signaling as a contributor to age-associated muscle dysfunction and support a context-dependent shift from adaptive CaMKII signaling in youth to maladaptive signaling in aging, consistent with antagonistic pleiotropy.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70704"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917658","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}

引用次数: 0

Secreted Frizzled-Related Protein 2 (SFRP2) Induces Follistatin-Like 1 (FSTL1) to Regulate Dihydrotestosterone (DHT)-Induced Dermal Papilla Cell Mitochondrial Dysfunction and Senescence. 分泌卷曲相关蛋白2 （SFRP2）诱导卵泡抑素样1 （FSTL1）调节双氢睾酮（DHT）诱导的真皮乳头细胞线粒体功能障碍和衰老

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70666

Youming Huang, Qiong Bian, Yeyu Shen, Xiaoxia Ding, Yan Teng, Danfeng Xu, Xianhong Yang, Yibin Fan

{"title":"Secreted Frizzled-Related Protein 2 (SFRP2) Induces Follistatin-Like 1 (FSTL1) to Regulate Dihydrotestosterone (DHT)-Induced Dermal Papilla Cell Mitochondrial Dysfunction and Senescence.","authors":"Youming Huang, Qiong Bian, Yeyu Shen, Xiaoxia Ding, Yan Teng, Danfeng Xu, Xianhong Yang, Yibin Fan","doi":"10.1111/acel.70666","DOIUrl":"10.1111/acel.70666","url":null,"abstract":"Androgenetic alopecia (AGA) is the most common form of non-scarring hair loss, driven by genetic factors and increased sensitivity of scalp hair follicles to dihydrotestosterone (DHT), which causes progressive miniaturization of dermal papilla cells and shortens the hair growth phase. The precise molecular pathogenesis of AGA remains incompletely understood. The study aimed to elucidate the regulatory mechanism between secreted frizzled-related protein 2 (SFRP2) and follistatin-like 1 (FSTL1), explore their impact on DHT-induced mitochondrial dysfunction and senescence in dermal papilla cells (DPCs), elucidate the effect of the SFRP2-FSTL1 axis on oxidative stress-related DPCs changes, and identify new therapeutic targets for AGA treatment. In the study, SFRP2 was highly expressed in the DPCs of AGA patients. Knocking down SFRP2 improved hair regeneration and follicle morphology within AGA model mice, promoting proliferation, migration, and invasion of DPCs in vitro. SFRP2 knockdown also alleviated inflammation, senescence, mitochondrial dysfunction, and oxidative stress. SFRP2 was found to bind to FSTL1, thereby promoting FSTL1 protein stability. Knocking down FSTL1 counteracted the negative effects of SFRP2 overexpression in vitro. In conclusion, SFRP2 emerges as a critical regulator in AGA by promoting stability and activity of FSTL1, establishing a novel SFRP2-FSTL1 axis that exacerbates DHT-driven pathogenic changes in DPCs. These findings identify SFRP2 and FSTL1 as key mediators of androgen-induced cellular dysfunction and suggest that disrupting this axis could offer a promising therapeutic strategy for slowing or reversing the progression of AGA.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70666"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890496","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}

引用次数: 0

Tissue-Level Transcriptomic Entropy Reveals Organ-Specific Aging Patterns and Predicts Cancer Progression. 组织水平的转录熵揭示器官特异性衰老模式并预测癌症进展。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70696

Gabriel Arantes Dos Santos, José Pedro Castro, Gabriela D A Guardia, Filipe F Dos Santos, Alexander Birbrair, Pedro A F Galante

{"title":"Tissue-Level Transcriptomic Entropy Reveals Organ-Specific Aging Patterns and Predicts Cancer Progression.","authors":"Gabriel Arantes Dos Santos, José Pedro Castro, Gabriela D A Guardia, Filipe F Dos Santos, Alexander Birbrair, Pedro A F Galante","doi":"10.1111/acel.70696","DOIUrl":"10.1111/acel.70696","url":null,"abstract":"Although aging and cancer share complex molecular mechanisms, distinguishing causative factors from byproducts remains challenging. Here, we investigated the role of tissue transcriptomic entropy-a measure of transcriptional disorder-in aging and cancer processes by analyzing RNA-sequencing data from over 25,000 samples from human and mouse tissues. We found that entropy changes during aging are highly tissue-specific, with some tissues showing increased entropy while others exhibit decreased or stable entropy levels. Moreover, transcriptomic entropy strongly correlates with age-related processes, showing positive associations with proliferation, cellular senescence, somatic mutation burden, and cellular reprogramming, whereas it negatively correlates with stemness. In cancer, we observed that primary tumors generally display higher entropy than normal tissue, with its levels further increasing in metastatic stages. Cancer treatment modulated entropy patterns in multiple contexts, with changes suggesting a role for transcriptional complexity in tumor plasticity and therapy resistance. Elevated entropy levels predicted poor survival outcomes in multiple cancer types, suggesting its potential as a prognostic marker. Furthermore, differential expression analysis revealed that entropy-associated genes are enriched in developmental processes and depleted in metabolic pathways, indicating a possible link to cellular dedifferentiation. Finally, we found increased entropy in various age-related disorders beyond cancer, suggesting that transcriptomic entropy may be a common feature in age-related diseases. Our findings establish transcriptomic entropy as a fundamental parameter in aging and cancer progression, offering new insights into disease mechanisms.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70696"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890483","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}

引用次数: 0

Midlife Growth Hormone Receptor Ablation Extends Healthy Lifespan and Induces Sex-Specific Hepatic Transcriptional Changes at Single-Cell Resolution. 中年生长激素受体消融术可延长健康寿命，并在单细胞分辨率下诱导性别特异性肝脏转录变化。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70695

Silvana Duran-Ortiz, Edward O List, Jonathan A Young, Yuji Ikeno, Shouan Zhu, Todd McHugh, Patrick M O'Connor, Minhoo Kim, Bérénice A Benayoun, Fabian Benencia, Reetobrata Basu, Emmanuel A Gotte, Darlene E Berryman, John J Kopchick

{"title":"Midlife Growth Hormone Receptor Ablation Extends Healthy Lifespan and Induces Sex-Specific Hepatic Transcriptional Changes at Single-Cell Resolution.","authors":"Silvana Duran-Ortiz, Edward O List, Jonathan A Young, Yuji Ikeno, Shouan Zhu, Todd McHugh, Patrick M O'Connor, Minhoo Kim, Bérénice A Benayoun, Fabian Benencia, Reetobrata Basu, Emmanuel A Gotte, Darlene E Berryman, John J Kopchick","doi":"10.1111/acel.70695","DOIUrl":"10.1111/acel.70695","url":null,"abstract":"Suppression of growth hormone (GH) signaling is known to be effective to extend lifespan in mammals, yet most models rely on congenital disruption of the GH/insulin-like growth factor-1 (IGF-1) axis. Whether modulation of this pathway later in life can still influence aging and the underlying cellular mechanisms remains incompletely understood. To address this, we ablated the growth hormone receptor (Ghr) at 12-months of age in mice (12mGHRKO), using a tamoxifen-inducible model. Midlife Ghr disruption produced the expected endocrine signature of GH resistance, including reduced circulating IGF-1 and elevated GH levels. Importantly, lifespan was significantly extended in both sexes without major effects on somatic growth. Despite increased adiposity, male 12mGHRKO mice exhibited improved insulin sensitivity and protection against age-related deterioration of neuromuscular performance and bone microarchitecture. Single-nucleus RNA sequencing (snRNA-seq) of liver tissue identified a reduction of B-cells in both sexes and a dimorphic transcriptional remodeling, including a shift toward feminized gene expression in male hepatocytes, marked by reduced male-biased gene expression and increased female-biased transcriptional programs, consistent with impaired pulsatile GH-STAT5 signaling. Together, these findings demonstrate that suppression of GH signaling initiated in middle age is sufficient to reshape hepatic transcriptional programs and promote healthy longevity, supporting the GH/IGF-1 axis as a promising target for gerotherapeutic interventions.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70695"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890444","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}

引用次数: 0

SIRT1 Silences L1 Retrotransposons by Stabilizing Heterochromatin-Modifying Complexes. SIRT1通过稳定异染色质修饰复合物沉默L1反转录转座子。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70689

Xiaona Wang, Tianbo Li, Huanyin Tang, Meng Xiao Liu, Qinghua Peng, Xiao Huang, Zhiyong Mao, Ying Jiang, Anke Geng

{"title":"SIRT1 Silences L1 Retrotransposons by Stabilizing Heterochromatin-Modifying Complexes.","authors":"Xiaona Wang, Tianbo Li, Huanyin Tang, Meng Xiao Liu, Qinghua Peng, Xiao Huang, Zhiyong Mao, Ying Jiang, Anke Geng","doi":"10.1111/acel.70689","DOIUrl":"10.1111/acel.70689","url":null,"abstract":"SIRT1, a sirtuin family member, has been extensively documented to be closely linked to aging and aging-related disease. Cellular senescence is a state of irreversible cell cycle arrest that functions as a key driver of aging. During cellular senescence, LINE-1 (L1) retrotransposable elements become transcriptionally activated and stimulate a type-I interferon (IFN-I) response. L1 activity has been strongly linked to aging and a variety of age-related disorders. However, whether SIRT1 influences cellular senescence through the transposable element L1 remains unknown. In this study, we discovered that SIRT1 significantly suppresses L1 retrotransposition. Under quiescent conditions, SIRT1 exhibits increased enrichment at the L1 5'-UTR region. This recruitment enhances its interaction with the heterochromatin-regulatory factors Lamin B1 and KAP1, subsequently elevating H3K9me3 levels. This repressive chromatin mark inhibits L1 transcription, thereby maintaining genomic stability and delaying cellular senescence. Consistent with these observations, SIRT1-deficient cell lines exhibited a marked reduction of the interaction of Lamin B1 and KAP1 and a reduced presence of these factors at the L1 5'-UTR. Consequently, the elevated L1 transcription resulting from SIRT1 deficiency activated the cGAS-STING pathway and ultimately triggered cellular senescence, an effect that was rescued by treatment with 3TC (a nucleoside reverse transcriptase inhibitor). In summary, our findings demonstrate that SIRT1 suppresses L1 retrotransposition by recruiting heterochromatin factors, thereby delaying cellular senescence and providing new insights with implications for delaying aging and mitigating age-related pathologies.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70689"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13526325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856800","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}

引用次数: 0

NAD⁺ Metabolic Reprogramming Drives CD8⁺ T Cells Senescence and Exacerbates Ulcerative Colitis. NAD+代谢重编程驱动CD8+ T细胞衰老并加剧溃疡性结肠炎

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70706

Maolin Ye, Qi Zhou, Mingjia Kong, Suhan Zhao, Lingxi Lin, Lirong Chen, Jianghong Yu, Feifei Luo, Jie Liu, Jun Zhang

{"title":"NAD+ Metabolic Reprogramming Drives CD8+ T Cells Senescence and Exacerbates Ulcerative Colitis.","authors":"Maolin Ye, Qi Zhou, Mingjia Kong, Suhan Zhao, Lingxi Lin, Lirong Chen, Jianghong Yu, Feifei Luo, Jie Liu, Jun Zhang","doi":"10.1111/acel.70706","DOIUrl":"10.1111/acel.70706","url":null,"abstract":"While immunosenescence is increasingly implicated in chronic inflammatory disorders, its precise pathogenic contribution to ulcerative colitis (UC) remains elusive. Here, we identify senescent CD8+ T cells as a distinct pathogenic population that exacerbates colitis, demonstrating that systemic senolytic treatment significantly attenuates disease severity. Mechanistically, nicotinamide adenine dinucleotide (NAD+) metabolic dysregulation triggers mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, promoting CD8+ T cell senescence through the activation of the cGAS-STING signaling pathway. Spatial transcriptomic mapping reveals that senescent CD8+ T cells are enriched within mucosal niches experiencing NAD+ metabolic dysregulation. Crucially, this senescent-metabolic signature correlates with severe disease phenotypes and predicts non-response to biologic therapies in UC patients. Collectively, our findings uncover a critical NAD+-cGAS-STING axis driving T cell senescence, establishing the clearance of senescent immune cells as a promising therapeutic strategy for UC.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70706"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13558662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917741","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}

引用次数: 0

Rethinking Senescence Hallmarks in the Brain: Lessons From Peripheral Tissues and Challenges in Defining Neuronal Senescence. 重新思考大脑中的衰老特征：来自外周组织的经验教训和定义神经元衰老的挑战。

IF 7.1 1区医学

Aging Cell Pub Date : 2026-09-01 DOI: 10.1111/acel.70719

Miraj Ud Din Momand, Kristina Macova, Dominika Fricova

{"title":"Rethinking Senescence Hallmarks in the Brain: Lessons From Peripheral Tissues and Challenges in Defining Neuronal Senescence.","authors":"Miraj Ud Din Momand, Kristina Macova, Dominika Fricova","doi":"10.1111/acel.70719","DOIUrl":"10.1111/acel.70719","url":null,"abstract":"Cellular senescence is increasingly recognized as a fundamental driver of aging and age-related diseases. Studies in peripheral tissues have revealed that senescence is not a uniform cellular state, but a highly heterogeneous phenotype shaped by distinct combinations of DNA damage, mitochondrial dysfunction, chromatin remodeling, impaired proteostasis, and diverse senescence-associated secretory phenotype. This heterogeneity critically influences both the identification and therapeutic targeting of senescent cells. As senescent cells accumulate with age, they contribute to chronic low-grade inflammation and tissue dysfunction, while their selective elimination can improve health span, establishing senescence as both a pathogenic mechanism and a therapeutic target in systemic aging. Emerging evidence now suggests that post-mitotic neurons and other neural cell types can acquire senescence-like states during aging and neurodegeneration. However, the direct application of canonical peripheral senescence markers to the nervous system remains conceptually and experimentally problematic, raising the risk of inconsistent or misleading interpretations across models and studies. In this review, we integrate insights from peripheral senescence biology to examine how cell type, inducing stressor, and experimental context shape senescence-associated phenotypes across neural systems, including in vitro models, physiologically aged brains, and models of Alzheimer's and Parkinson's disease. By critically evaluating where canonical senescence hallmarks translate and where they fail to translate to post-mitotic neurons, we propose that a refined, neuron-centered framework is essential for moving the field beyond descriptive observations and for rigorously testing the causal contribution of senescent neural cells to neurodegeneration.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70719"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13569990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954494","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}

引用次数: 0