Aging Cell最新文献

{"title":"Histone Modifications at the Intersection of Aging, Neuroinflammation and Metabolism in Alzheimer's Disease","authors":"Junyi Liang,&nbsp;Huawen Cao,&nbsp;Xiumin Ren,&nbsp;Nan Sha,&nbsp;Xueqing Han,&nbsp;Ling Jiang,&nbsp;Bin Liu,&nbsp;Weiming Zhao","doi":"10.1111/acel.70785","DOIUrl":"https://doi.org/10.1111/acel.70785","url":null,"abstract":"<p>Aging, neuroinflammation and metabolic dysfunction are tightly intertwined in Alzheimer's disease (AD), but how transient pathological signals become persistent cellular states remains poorly understood. Histone post-translational modifications (PTMs) provide a dynamic interface between extracellular stimuli, cellular metabolism and chromatin state. This Review examines how canonical histone modifications and emerging metabolite-derived acylations regulate inflammatory and stress-responsive programmes across microglia, astrocytes and neurons during aging and AD. We discuss how amyloid-β, tau pathology, metabolic dysfunction and innate immune signaling converge on histone-modifying machinery, and how reciprocal interactions between metabolism and chromatin may stabilize disease-associated cell states. Particular attention is given to cellular senescence and neuroimmune memory, while emphasizing the context dependence of individual histone marks across cell types, genomic regions and disease stages. We further evaluate evidence for causality using three criteria: perturbation, persistence and reversibility. This framework distinguishes chromatin states that accompany ongoing pathology from those capable of sustaining pathological cell states beyond their initiating signals. Finally, we consider therapeutic strategies targeting histone-modifying enzymes, chromatin readers and metabolic inputs to restore chromatin plasticity and promote resolution of chronic neuroinflammation.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70785","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259253","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":"FGF13 Alleviates the Aging Process in Mice by Regulating Astrocyte Function in the Medial Prefrontal Cortex via Phafin2 Signaling Pathway","authors":"Rui Zheng,&nbsp;Zheng Tu,&nbsp;Yang Fang,&nbsp;Caixiang Zhuang,&nbsp;Yuchao Zhang,&nbsp;Yibo Ying,&nbsp;Zhiyi Feng,&nbsp;Ziyang Jin,&nbsp;Yanyan Zheng,&nbsp;Zhouguang Wang","doi":"10.1111/acel.70784","DOIUrl":"https://doi.org/10.1111/acel.70784","url":null,"abstract":"<p>Aging is an intrinsic biological process; specifically, brain aging leads to cognitive decline, memory loss, and numerous neurodegenerative diseases. Fibroblast growth factor 13 (FGF13) is expressed in the central nervous system (CNS) and plays a critical role in several neuropathological conditions; however, the specific role of FGF13 in brain aging remains unclear. In this study, screening of public gene expression databases revealed that <i>FGF13</i> is significantly downregulated in the brain tissues of aging mice and macaques, particularly within the medial prefrontal cortex (mPFC) and astrocytes. Specific knockout of <i>FGF13</i> in cortical astrocytes accelerates the aging phenotype and impairs neurological function in mice. Conversely, overexpression of FGF13 effectively delays the aging process and ameliorates aging-induced cognitive impairment. RNA-seq analysis indicated that FGF13 primarily influences astrocyte-mediated inflammatory responses and cellular autophagy. Mechanistically, FGF13 targets and binds to Phafin2, promoting autophagy in astrocytes. Homeostatic astrocytes not only ameliorate neuronal damage but also reduce the release of inflammatory factors by microglia, playing a crucial role in mitigating the aging process in mice. In summary, FGF13 improves the cerebral microenvironment by regulating astrocyte function, ultimately exerting an anti-aging effect. These findings provide a theoretical basis for neuroscience and aging research, offering new insights into age-related genetic phenotypes in the brain and body, as well as the interplay between aging and various diseases.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70784","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149258771","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":"Metabolomic Signatures of Longevity in Bivalves Reveal Reorganization of TCA Cycle and Amino Acid Metabolism","authors":"Pauline Bertrand,&nbsp;Clément J. L. Chevret,&nbsp;Enrique Rodríguez,&nbsp;Hélène Lemieux,&nbsp;Pierre U. Blier","doi":"10.1111/acel.70772","DOIUrl":"https://doi.org/10.1111/acel.70772","url":null,"abstract":"<p>Mitochondria are central regulators of cellular metabolism, integrating energy production, redox balance, and signaling pathways that shape aging trajectories. If mitochondrial organization contributes to lifespan divergence, exceptionally long-lived species should exhibit distinctive metabolic signatures reflecting adaptations promoting long-term cellular maintenance. Comparative approaches across species with extreme lifespan variation provide a powerful framework for identifying potential metabolic strategies underlying longevity. We conducted targeted metabolomic profiling of five marine bivalve species spanning a lifespan gradient from approximately 30 to more than 500 years, including the exceptionally long-lived ocean quahog, <i>Arctica islandica</i>. Fifty metabolites were quantified in gill and mantle tissue to determine whether lifespan variation is associated with coordinated changes in metabolic organization. Lifespan emerged as a dominant axis of metabolomic variation across species. Long-lived bivalves exhibited a distinct metabolic phenotype characterized by a global reduction in free amino acid pools and coordinated changes in metabolites associated with mitochondrial metabolism. Longevity was associated with increased succinate-to-fumarate ratios, reduced fumarate and malate concentrations, and reduced engagement of pyruvate-derived anaerobic pathways under basal conditions. Although these patterns varied in magnitude across tissues, they converged on a common longevity-associated metabolic signature. Together, these patterns suggest that exceptional longevity is associated with a distinct organization of mitochondrial-related metabolism and a more selective allocation of metabolic resources, rather than a generalized suppression of metabolism. Our findings identify metabolomic signatures associated with exceptional longevity across the bivalve species studied and support the hypothesis that long lifespan is characterized by a distinctive metabolic architecture favoring long-term cellular maintenance.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70772","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149258770","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":"Nonlinear Aging of the Human TCR Repertoire Is Influenced by Sex, CMV, and Cancer","authors":"Naja Lange,&nbsp;Asbjørn K. Attermann,&nbsp;Randi Istrup Juul,&nbsp;Laura Andersen,&nbsp;Iver Nordentoft,&nbsp;Leon Eyrich Jessen,&nbsp;Nicholas McGranahan,&nbsp;Hugo J. W. L. Aerts,&nbsp;Lars Dyrskjøt,&nbsp;Nicolai J. Birkbak","doi":"10.1111/acel.70777","DOIUrl":"https://doi.org/10.1111/acel.70777","url":null,"abstract":"<p>Aging is accompanied by a progressive decline in immune function, increasing susceptibility to infections, cancer, and poorer treatment outcomes. The diversity of the T cell receptor (TCR) repertoire, reflecting the capacity to recognize diverse antigens, is known to decline with age. However, how intrinsic and extrinsic factors jointly shape TCR diversity and its rate of decline, as well as the extent to which this diversity influences clinical outcomes in cancer, remain poorly characterized. Here, we integrate TCR sequencing data from 1.32 billion unique T cell clones, derived from 798 patients with cancer and 5052 individuals without cancer across 14 independent cohorts, to systematically characterize the effects of age, sex, and chronic cytomegalovirus (CMV) infection on peripheral blood repertoire diversity. We identify a nonlinear trajectory of diversity loss that accelerates after midlife, with a marked increase in the rate of decline beyond approximately 50 years of age, which is further modified by sex and CMV infection. In patients with cancer, higher peripheral TCR diversity was associated with improved overall survival across multiple cancer types, even when accounting for the impact of age, sex, and CMV on diversity. Together, these findings underline peripheral TCR repertoire diversity as a dynamic marker of immune aging shaped by demographic and chronic viral factors.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70777","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149258699","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":"Live Fast, Die Old: Lowering Insulin Signalling During Development Can Speed Growth, Increase Reproduction and Lifespan, but Impair Environmental Sensing and Harm Offspring in Caenorhabditis elegans","authors":"Sara D. Irish,&nbsp;Annabel Kimberley,&nbsp;Peter Lenart,&nbsp;Hanne Carlsson,&nbsp;Anna Braybrooke,&nbsp;Benjamin Towbin,&nbsp;Simone Immler,&nbsp;Alexei A. Maklakov","doi":"10.1111/acel.70783","DOIUrl":"10.1111/acel.70783","url":null,"abstract":"<p>Genetic trade-offs can constrain life-history evolution resulting in the evolution of ageing. Reduced insulin/insulin-like signalling (rIIS) improves somatic maintenance and dramatically increases lifespan in <i>Caenorhabditis elegans</i>, but the effects on fitness are unclear. Here we used a novel experimental approach to show that, contrary to the prevailing paradigm, rIIS via <i>daf-2</i> RNAi during development can improve development, reproduction, survival, individual fitness, and population growth rate in the laboratory and semi-natural conditions. However, developmental rIIS extends lifespan and improves fitness only in some temperatures, which explains why our results differ from previous findings. Furthermore, while developmental rIIS can improve a suite of life-history traits in parents, it slows down offspring development. Finally, because rIIS interferes with environmental sensing and compromises adaptive developmental plasticity in response to stress, a central part of <i>C. elegans</i> life history in nature, the ability to sense the environment correctly during development comes at the cost of accelerated senescence. These results suggest the complexity of gene-by-environment interactions during development imposes constraints on molecular signalling networks leading to genetic trade-offs across the life course that natural selection in late-life is unable to resolve. However, these constraints can be resolved by artificially fine-tuning gene expression at different ages.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70783","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149242085","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":"In Vivo Partial Cell Reprogramming With Yamanaka Factors Reduced Ischemic Brain Damage in Aging Mice","authors":"Paula R. Mallavibarrena,&nbsp;Gerardo Martín-López,&nbsp;Jorge Rodríguez-Morales,&nbsp;Jesús Ávila,&nbsp;Félix Hernández,&nbsp;María José Pérez-Álvarez","doi":"10.1111/acel.70776","DOIUrl":"https://doi.org/10.1111/acel.70776","url":null,"abstract":"<p>Aging is associated with functional decline and reduced regenerative capacity in the brain, is also the strongest risk factor for ischemic stroke, which remains a leading cause of mortality and long-term disability worldwide, and is associated with impaired functional recovery. Here, we investigated whether short-term partial cellular reprogramming through cyclic expression of Yamanaka factors (OSKM) in a Tet-ON mouse model under Rosa-26 promoter has any impact on ischemic damage in aged mice. To assess ischemic resilience, mice underwent permanent middle cerebral artery occlusion (pMCAo). Forty-eight hours after ischemia, OSKM-induced mice displayed significantly smaller damaged area compared with wild-type controls, accompanied by improved neurological scores and enhanced performance in the tightrope test, suggesting preserved sensorimotor abilities. Notably, myelin integrity was preserved in OSKM-treated mice, as shown by Black-Gold staining and stable MAG and MBP expression, whereas wild-type mice exhibited pronounced demyelination. Given the role of oligodendrocytes in myelin maintenance, we quantified the abundance of their different populations. OSKM induction significantly increased total oligodendrocytes (Olig2⁺) and oligodendrocyte precursor cells (PDGFRα⁺) following ischemia, suggesting an enhanced reparative response. Moreover, partial reprogramming preserved neuronal density in the ischemic cortex and prevented the marked astrocytic activation observed in wild-type mice, while microglial responses remained comparable across genotypes. These findings demonstrate that cyclic partial reprogramming in aged mice reduces ischemic damage, highlighting OSKM induction as a promising strategy for enhancing brain resilience during cerebrovascular accidents.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70776","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149258489","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":"Genome Aging in Women: Hematopoietic Loss of X Chromosome as An Exemplar","authors":"Xihan Guo,&nbsp;Xueqin Dai","doi":"10.1111/acel.70778","DOIUrl":"https://doi.org/10.1111/acel.70778","url":null,"abstract":"<p>Genome aging refers to age-related acquisition and expansion of <i>de novo</i> mutations in somatic cells, and is now increasingly viewed as a central driver of organismal aging. Loss of X chromosome (LOX), the state in which one X chromosome (ChrX) is missing, represents the most common genetically inferred type of acquired mutation in women. Recent technological advancements, along with the growing availability of large-scale cohorts for association studies, have provided powerful new insights into this phenomenon. The frequency and clone size of LOX increase significantly with age: with over 10% of women aged 55 years or older showing detectable LOX in blood. LOX preferentially affects the inactivated ChrX derived from either parent, or in some cases, affects the ChrX from one specific parent. Besides aging, the acquisition and expansion of LOX are shaped by factors related to ChrX itself, genome-wide inherited and acquired variants, and lifestyle and environmental stressors. Due to the critical biological roles of ChrX, even in its inactive state, LOX impairs cellular functions and is strongly linked to hematological malignancies and a range of benign diseases. Understanding the mechanisms driving the causes and consequences of LOX may expand the sex-biased genomic architecture of aging and uncover strategies for disease prevention in women. In this review, by integrating the most recent progress in LOX studies with unique biology of ChrX and perspectives from aneuploidy, we provide a synthesized and updated understanding of the rise, expansion and consequences of blood LOX, while also posing key questions for future research.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70778","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222839","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":"Featured Cover","authors":"Yaoyu Zhang,&nbsp;Jialiang Zhang,&nbsp;Yanjiani Xu,&nbsp;Wenhua Lei,&nbsp;Fei Xu,&nbsp;Junli Li,&nbsp;Zisong Wei,&nbsp;Bo Su,&nbsp;Shuang Liu,&nbsp;Jing Zhou,&nbsp;Hongde Li,&nbsp;Junpeng Ran,&nbsp;Weiya Li,&nbsp;Tuerhongjiang Tuerdi,&nbsp;Xiaojiao Wang,&nbsp;Zhi Fang,&nbsp;Fangyang Huang,&nbsp;Mao Chen","doi":"10.1111/acel.70779","DOIUrl":"https://doi.org/10.1111/acel.70779","url":null,"abstract":"<p>Cover legend: The cover image is based on the article <i>The Senokine Gas6 Promotes Aortic Valve Calcification Through CaMKII–DRP1–Mediated Terminal Scission of Mitochondrial-Derived Vesicles</i> by Yaoyu Zhang <i>et al.,</i> https://doi.org/10.1111/acel.70758.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70779","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222837","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":"Cellular Senescence Dysregulates Antiviral Interferon Responses in Idiopathic Pulmonary Fibrosis","authors":"Jun-Wei B. Hughes,&nbsp;Yasmina Reisser,&nbsp;Franziska Hornung,&nbsp;Tyler A. U. Hilsabeck,&nbsp;Fiona Senchyna,&nbsp;Ana L. Coelho,&nbsp;Tsung-Che Ho,&nbsp;Kevin Schneider,&nbsp;David Furman,&nbsp;Cory M. Hogaboam,&nbsp;Claude Jourdan Le Saux,&nbsp;Pierre-Yves Desprez,&nbsp;Stefanie Deinhardt-Emmer","doi":"10.1111/acel.70763","DOIUrl":"https://doi.org/10.1111/acel.70763","url":null,"abstract":"<p>Patients with idiopathic pulmonary fibrosis (IPF) are highly vulnerable to respiratory virus infections, but the cellular mechanisms linking fibrotic remodeling to impaired local antiviral defense remain unclear. Here, we investigated how cellular senescence shapes the response of patient-derived healthy (HLF) and IPF primary lung fibroblasts to influenza A virus (IAV) infection. Transcriptomic profiling identified infection as the driver of gene expression in both DNA damage-induced senescent HLF and IPF fibroblasts and revealed induction of canonical antiviral pathways in both cell states. However, senescent IPF fibroblasts adopted a distinct antiviral response state characterized by a broader set of uniquely induced genes and differential coordination of antiviral transcriptional networks. Functionally, senescence increased viral titers in HLF and IPF fibroblasts, while senescent IPF fibroblasts displayed an altered inflammatory response. Network analysis linked viral response- and cell cycle-associated modules specifically to the senescent HLF infected state, whereas these programs were weaker in senescent IPF fibroblasts. Transcription factor inference identified <i>IRF3</i> and <i>STAT1</i> as candidate regulators of this altered antiviral state in both senescent HLF and IPF fibroblasts. Consistent with the network and transcription factor analyses, siRNA-mediated depletion of <i>IRF3</i> or <i>STAT1</i> significantly reduced IFN-β secretion in senescent HLF fibroblasts, whereas IPF fibroblasts showed only milder effects, indicating a disease-specific dependence on these pathways for antiviral control. Together, these findings show that the combination of cellular senescence and fibrotic fibroblast identity creates a dysfunctional antiviral state that may help explain the high susceptibility of IPF patients to virus-associated acute exacerbations and disease worsening.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70763","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222742","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 Cilia–Centered Nicotinamide Adenine Dinucleotide (NAD+) Signaling Network Regulates Hypothalamic Lysosomal Homeostasis and Metabolic Aging","authors":"Se Eun Park,&nbsp;Eun Roh,&nbsp;Jae Woo Park,&nbsp;Seong Jun Kim,&nbsp;So Yeon Jeong,&nbsp;Chae Beom Park,&nbsp;Hyo Sun Lim,&nbsp;Ji Soo Kim,&nbsp;Mun Gyeom Kim,&nbsp;Myeong Ju Kim,&nbsp;Young In Cho,&nbsp;Wontae Jeong,&nbsp;Gil Myoung Kang,&nbsp;Sang-Yeob Kim,&nbsp;Se Hee Min,&nbsp;Min-Seon Kim","doi":"10.1111/acel.70745","DOIUrl":"https://doi.org/10.1111/acel.70745","url":null,"abstract":"<p>Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite that regulates diverse cellular metabolic processes. Primary cilia, hair–like organelles on the cell surface, function as critical signaling hubs. Here, we demonstrate that cellular NAD⁺ levels are key regulators of both primary cilia growth and lysosomal function in hypothalamic neurons. NAD⁺ depletion induces ciliary shortening and diminishes lysosomal activity in a cilia–dependent manner. Mechanistically, the lysosomal repair complex protein CHMP4B translocates from periciliary satellites to lysosomes during lysosomal stress, a process impaired by ciliary dysgenesis. Disrupted lysosomal recruitment of CHMP4B leads to abnormal lysosomal Ca²⁺ signaling and lysosomal dysfunction. Aged mice with hypothalamic NAD⁺ deficiency exhibit shortened cilia and lysosomal stress phenotypes, both of which are restored by calorie restriction (CR). Moreover, CR improves aging–associated metabolic dysfunction, at least in part, through hypothalamic cilia–dependent mechanisms. These findings identify a primary cilium–mediated–NAD⁺ signaling axis that maintains lysosomal homeostasis in hypothalamic neurons, the disruption of which drives metabolic aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 11","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70745","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222739","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}