Aging Cell最新文献

{"title":"Lactiplantibacillus plantarum AS21 Attenuates Sex-Biased Glucose Intolerance in Aging Mice via Gut Mucosal Microbiota-Derived Citrulline.","authors":"Mengya Jia, Mengyan Chen, Hu Chen, Huiling Zhang, Ruixue Dou, Chaorui Wang, Muhammad Ishaq, Xiaoying Wei, Zitong Ding, Xusheng Guo","doi":"10.1111/acel.70662","DOIUrl":"10.1111/acel.70662","url":null,"abstract":"<p><p>Aging-related metabolic decline, particularly impaired glucose tolerance, represents a growing challenge in aging populations. Probiotics are promising modulators of host metabolism; however, how sex differences influence their efficacy in mitigating metabolic aging remains poorly understood. Here, we administered Lactiplantibacillus plantarum AS21 to naturally aged male and female mice for 6 months. We observed a pronounced sexual dimorphism in metabolic decline, with aged males exhibiting more severe glucose intolerance than females. Concurrently, circulating citrulline levels were depleted in males but elevated in females. AS21 intervention significantly ameliorated glucose intolerance in aged males, while exerting minimal effects on metabolically stable females. Microbiota analysis revealed that AS21 reshaped the mucosa-associated microbial communities in males, an effect accompanied by increased abundance of microbial citrulline biosynthesis genes (argF, argI) and restoration of circulating citrulline. In contrast, females maintained stable metabolic and citrulline profiles alongside limited microbial alterations. Furthermore, direct citrulline supplementation recapitulated these metabolic benefits, improving glucose tolerance, enhancing glucose-stimulated insulin secretion (GSIS), and stimulating glucagon-like peptide-1 (GLP-1) release. Collectively, these findings demonstrate that AS21 alleviates age-related glucose dysregulation in male mice-a benefit closely associated with the restoration of microbiota-driven citrulline metabolism. This highlights its potential as a sex-specific, microbiota-targeted strategy for managing metabolic aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 8","pages":"e70662"},"PeriodicalIF":7.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757068","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":"Ovarian Extracellular Matrix Mechanics Regulate Oocyte-Follicle Interactions During Female Reproductive Aging.","authors":"Xingyu Shen, Haiyang Wang, Gefei Cao, Yaelim Lee, Jin Zhu, Loo Chien Wang, Tianyun Zhao, Siok Ghee Ler, Radoslaw M Sobota, Rong Li, Jennifer L Young","doi":"10.1111/acel.70668","DOIUrl":"10.1111/acel.70668","url":null,"abstract":"<p><p>Female reproductive aging is associated with ovarian functional decline, leading to infertility. During aging, biochemical and biophysical changes in the ovarian extracellular matrix (ECM) occur, yet how these properties affect follicle growth and oocyte quality remains poorly understood. Here we describe spatiotemporal changes in the ovarian ECM with age using mass spectrometry, immunohistochemistry, and nanoindentation. While follicle stiffness remains unchanged, stromal matrix remodeling is associated with a ~2.5-fold increase in stiffness. To understand how this increase in stromal stiffness affects age-related follicular dysfunction, isolated young follicles were cultured in soft and stiff hydrogels mimicking young and aged ovarian stromal stiffness, respectively. Higher stiffness lead to a decrease in granulosa cell (GC) proliferation, oocyte quality, and GC-oocyte interactions mediated via transzonal projections (TZPs). RNA-seq revealed TGF-β signaling as a major pathway affected by stiffness, and activation of TGF-β signaling through Smad7 silencing rescued TZP formation and oocyte quality in stiff matrix. These findings provide mechanistic insight into how changes in ECM mechanics contribute to ovarian aging functional decline and reveal potential therapeutic targets to counter fertility loss associated with tissue aging and fibrosis.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 8","pages":"e70668"},"PeriodicalIF":7.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148719510","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":"Bidirectional Relationship and Shared Mechanisms Between Sarcopenia and Osteoporosis: An Observational Study Integrating Genomic, Proteomic, and Metabolomic Data.","authors":"Siqi Xu, Simin Wen, Xizeng Zong, Jianwei Zhu, Qiuling Du, Yu Li, Kunyan Wang, Peihua Cao, Changhai Ding, Yan Zhang, Guangfeng Ruan","doi":"10.1111/acel.70617","DOIUrl":"10.1111/acel.70617","url":null,"abstract":"<p><p>With global population aging, sarcopenia and osteoporosis have become critical public health challenges. Muscles and bones are closely interconnected anatomically and functionally, but the biological mechanisms connecting sarcopenia and osteoporosis have not yet been fully elucidated. This study systematically investigated the bidirectional relationship and shared mechanisms between sarcopenia and osteoporosis through multi-omics analysis integrating genomic, proteomic, and metabolomic data from the UK Biobank. Our findings indicated that the two conditions may act as reciprocal risk factors. Higher lean mass index (hazard ratio [HR] = 0.830, 95% confidence interval [CI]: 0.788-0.874), greater hand grip strength (HR = 0.544, 95% CI: 0.531-0.558) and faster usual walking pace (HR = 0.735, 95% CI: 0.723-0.746) were significantly associated with lower osteoporosis incidence, with multiple plasma proteins and metabolites identified as mediators in these associations. Conversely, higher bone mineral density of left heel (HR = 0.613, 95% CI: 0.394-0.946) and right heel (HR = 0.591, 95% CI: 0.380-0.912) were associated with reduced sarcopenia risk. We also observed a positive genetic correlation (r = 0.25, p = 1.6 × 10^-5) between sarcopenia and osteoporosis, as well as substantial overlaps in risk-associated genes and circulating biomarkers between the two conditions with consistent effect directions. Furthermore, modifiable factors including smoking, sleep duration, and physical activity exhibited similar effect patterns between sarcopenia and osteoporosis, with more than 30% overlap in mediating proteins and metabolites. These discoveries highlight common pathophysiological pathways potentially underlying both conditions and are expected to advance the understanding of muscle-bone interdependence.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70617"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13318683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148358564","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":"Spatial Transcriptomic Atlas Reveals That Forkhead Box O3-Mediated Mitochondrial Dynamics Imbalance Drives Premature Ovarian Insufficiency in Mice.","authors":"Ziwei Song, Yaoli Yin, Meilin Chen, Xiaolu Jin, Zemin Li, Hongxiao Li, Meihong Shen","doi":"10.1111/acel.70623","DOIUrl":"10.1111/acel.70623","url":null,"abstract":"<p><p>Premature ovarian insufficiency (POI) is a major driver of female reproductive aging, but its mechanisms and the spatial and structural patterns of reproductive aging remain poorly understood. This study, therefore, constructed a spatial transcriptomic atlas of POI mouse models to define the spatial and molecular features of granulosa senescence during disease progression. Spatial analysis revealed disrupted follicular structure and distinct granulosa subpopulations exhibiting blocked differentiation and senescence-associated gene signatures. Integrating multiple gene sets identified structural and functional mitochondrial impairment, excess fission, reduced fusion, mitochondrial membrane potential loss, insufficient ATP production, and reactive oxygen species accumulation as central features of granulosa senescence in POI. KEGG pathway enrichment implicated FOXO signaling in regulating mitochondrial dysfunction, and FOXO3 phosphorylation was significantly reduced in POI. In a triptolide-induced KGN cell POI model, pharmacological inhibition of aberrant FOXO3 activation partially restored mitochondrial morphology and function, whereas suppressing FOXO3 phosphorylation in normal KGN cells induced mitochondrial dysfunction. AAV-mediated FOXO3 overexpression in mouse granulosa cells recapitulated the senescent phenotype and mitochondrial dynamic imbalance, activating PINK1/PARKIN-mediated mitophagy signaling. Physiologically aged 10-month-old mouse ovaries showed identical hallmarks-reduced p-FOXO3, upregulated senescence markers, and disrupted mitochondrial dynamics-suggesting a conserved feature of ovarian functional decline. Together, these findings demonstrate that aberrant FOXO3 pathway activation disrupts mitochondrial dynamic homeostasis, driving granulosa senescence and ovarian failure in POI. By integrating spatial transcriptomics with functional and mechanistic analyzes, this study establishes a spatially resolved framework for understanding ovarian aging and identifies FOXO3-regulated mitochondrial pathways as potential diagnostic and therapeutic targets for POI.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70623"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13355553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417182","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":"Mesenchymal Stem Cell-Derived Exosomes Improve Aging-Related Changes in Liver Lipid Metabolism by Enhancing Autophagy.","authors":"Jinquan Li, Mengqi Gao, Jinke Feng, Dini Huo, Rui Hong, Fuhua Zhang, Qin He, Ming Dong","doi":"10.1111/acel.70642","DOIUrl":"10.1111/acel.70642","url":null,"abstract":"<p><p>Health problems associated with aging have become increasingly severe in recent years. For example, hepatic lipid metabolism declines as the body ages, leading to lipid metabolic disorders. Although exosomes have been explored for treating metabolic diseases, there is currently a paucity of research regarding aging-related changes in hepatic lipid metabolism. Herein, we cultured human umbilical cord mesenchymal stem cells (HucMSCs), from which we extracted HucMSC-derived exosomes (HucMDEs). We then established a natural aging mouse model in vivo and a palmitic acid-induced AML12 cell model in vitro; HucMDEs were subsequently used as an intervention. Western blot analysis and quantitative real-time PCR were used to investigate changes in liver lipid metabolism and senescence-related markers in vivo and in vitro. Our results revealed that the HucMDE-injected mice showed reduced body weights, increased insulin sensitivity, decreased hepatic lipid deposition, reduced senescence, and augmented autophagy levels compared with the aged group of mice. The in vitro results were consistent with the in vivo results. When autophagy-related genes were silenced in AML12 cells via small interfering RNAs, or when cells were treated with the autophagy inhibitor 3-methyladenine or the lysosomal inhibitor bafilomycin A1, HucMDEs were able to reverse the reduction in hepatocyte autophagy levels. In this study, we demonstrated that HucMDEs improved hepatic lipid metabolism and attenuated cellular senescence by enhancing autophagy. We expect that these findings will provide novel potential therapeutic targets for the treatment of hepatic lipid metabolism disorders during aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70642"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13375943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467931","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 Non-Canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver.","authors":"Sabira Mohammed, Chao Jiang, Travis Pennington, Shylesh Bhaskaran, Phoebe Ohene-Marfo, Kara F Kneuper, Constantin Georgescu, Kamille Pitts, Albert Tran, Zongkai Peng, Amit Singh, Zhibo Yang, Tiangang Li, Bethany Hannafon, Courtney Houchen, Jonathan D Wren, Andriy Yabluchanskiy, Veronica Galvan, Nagib Ahsan, Michael Kinter, Tommy L Lewis, Sathyaseelan S Deepa","doi":"10.1111/acel.70618","DOIUrl":"10.1111/acel.70618","url":null,"abstract":"<p><p>Liver aging is characterized by chronic inflammation and metabolic dysfunction that drive progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Necroptosis, a pro-inflammatory form of cell death via the Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1)-RIPK3-Mixed Lineage kinase domain Like pseudokinase (MLKL) pathway, is activated in aging livers, and systemic inhibition of this pathway reduces hepatic inflammation and pathology. The cell type-specific role of necroptosis in liver aging, however, is unclear. Notably, RIPK3 is suppressed in hepatocytes under metabolic disease, suggesting necroptosis independent functions for MLKL. Here, we show that MLKL is elevated in aged hepatocytes and drives liver aging via a non-necroptotic mechanism. Using hepatocyte-specific MLKL-overexpressing mice (MLKL^HepOE), we find that MLKL overexpression does not induce necroptosis but instead promotes cellular senescence, evidenced by increased p16INK4a and p21WAF1/Cip1 and elevated senescence associated secretory phenotype (SASP). Mechanistically, MLKL induces hepatocyte mitochondrial dysfunction, with impaired respiration, altered mitochondrial dynamics, and increased reactive oxygen species, implicating oxidative stress as a contributing mechanism. This mitochondrial stress is associated with enhanced release of pro-inflammatory extracellular vesicles (EVs) and induction of senescence in hepatocytes and non-parenchymal cells. While hepatocytes contribute substantially to total senescent burden by abundance, macrophages emerge as a senescence-enriched population, indicating amplification of senescence through non-cell-autonomous signaling. Collectively, these findings reveal a non-lethal, non-necroptotic function of hepatocyte MLKL in promoting liver inflammaging via mitochondrial dysfunction and paracrine senescence signaling, identifying MLKL as a regulator of hepatic aging and a potential therapeutic target in age-associated liver disease.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70618"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13331751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381237","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":"Karyopherin Dysfunction Is a Key Driver of Aging.","authors":"Louis R Lapierre","doi":"10.1111/acel.70634","DOIUrl":"10.1111/acel.70634","url":null,"abstract":"<p><p>Aging is often framed as the gradual erosion of proteostasis, driven by declining chaperone capacity, impaired degradation, and dysregulated protein synthesis. Yet this view implicitly assumes that proteins fail primarily because they misfold or escape clearance. Increasing evidence instead points to a more fundamental problem: aging disrupts the spatial management of the proteome. Gradually, proteins are misplaced, signaling pathways are uncoupled from their compartments, and condensates that were once dynamic become pathological. At the center of this spatial collapse lies nucleocytoplasmic protein partitioning. Nucleocytoplasmic protein transport has long been treated as a background housekeeping process, that is, essential but largely passive. However, this assumption is no longer reasonable. Karyopherins, the importins, exportins and biportins that mediate selective transport across the nuclear pore complex (NPC), are emerging as active regulators of proteostasis, phase behavior, and signaling fidelity. Rather than simply responding to cargo demand, karyopherins shape intracellular protein solubility, suppress aberrant condensation, and buffer age-associated stress. Their dysfunction therefore constitutes a primary, not secondary, driver of aging phenotypes. Here, I argue that karyopherins should be repositioned at the core of aging biology. I propose that age-dependent failure of karyopherin-mediated transport represents a unifying mechanism linking proteostasis collapse, altered gene regulation, and the emergence of age-associated diseases. This perspective redefines nucleocytoplasmic protein transport from a logistics challenge into a central regulatory layer and highlights karyopherins as emerging targets for aging interventions.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70634"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434665","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 Enhances Serotonergic Signaling via 5-HT₇ Receptors Underlying Mechanical Alloknesis.","authors":"Qiaofeng Zhao, Alberto Leguina-Ruzzi, Mitsutoshi Tominaga, Yayoi Kamata, Atsuko Kamo, Huiying Wan, Bin Yin, Yuping Ran, Kenji Takamori","doi":"10.1111/acel.70633","DOIUrl":"10.1111/acel.70633","url":null,"abstract":"<p><p>Chronic pruritus (or itch) is a common condition associated with aging; however, the neural mechanisms driving age-related itch hypersensitivity remain largely unknown. Here, we investigated the role of serotonergic signaling in modulating itch sensitivity during aging. Aged mice exhibited enhanced mechanical alloknesis without changes in spontaneous scratching behavior, indicating that aging selectively affects mechanically evoked itch. Consistent with this phenotype, aged mice showed elevated urinary serotonin levels and increased expression of the serotonin receptor 5-HT₇ in dorsal root ganglion neurons and the spinal dorsal horn. Pharmacological blockade of 5-HT₇ receptors attenuated itch-related behaviors, particularly mechanical alloknesis, indicating that serotonergic remodeling contributes to age-related itch hypersensitivity. These findings identify spinal 5-HT₇ signaling as a potential therapeutic target for chronic pruritus in older individuals.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70633"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434624","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":"Liver- and Immune-Enriched Molecular Signatures Associated With Mortality in Older Adults.","authors":"Yi-Long Huang, Wei-Ju Lee, Pei-Lin Lee, Li-Ning Peng, Fei-Yuan Hsiao, Liang-Kung Chen","doi":"10.1111/acel.70621","DOIUrl":"10.1111/acel.70621","url":null,"abstract":"<p><p>Quantifying biological aging requires biomarkers that capture multisystem physiological decline beyond chronological age. We aimed to compare the prognostic performance of plasma proteomics, metabolomics, and conventional clinical risk factors for all-cause mortality, and to characterize molecular pathways associated with mortality risk and age-related physiological decline. Untargeted plasma proteomics and metabolomics were profiled in 848 community-dwelling adults from the I-Lan Longitudinal Aging Study (ILAS), followed for a mean of 8.5 years, during which 92 deaths occurred. Cox proportional hazards models were applied to identify mortality-associated molecular features and their enriched biological pathways. We identified 79 proteins associated with all-cause mortality (FDR < 0.1), predominantly liver-derived and immune-related. Pathway analysis revealed coordinated dysregulation across coagulation cascades, complement activation, oxidative stress responses, glucose metabolism, and bile acid metabolism. Elastic net regression was subsequently used to construct omics-based mortality risk scores, which were further evaluated in an independent validation cohort from the Longitudinal Aging Study of Taipei (LAST). A 20-protein mortality score achieved strong discrimination (C-index 0.81), outperforming metabolite-based models (C-index 0.77) and clinical risk factors (C-index 0.73) in the discovery cohort. In the external validation cohort, both proteomic- and metabolomic-derived scores showed directionally consistent associations with mortality risk. Together, these findings identify liver- and immune-enriched molecular signatures associated with mortality risk in older adults and support the utility of plasma multi-omics profiling as a scalable precision tool for biological age assessment. The identified proteomic and metabolomic pathways may help inform future interventions targeting systemic aging and age-related functional decline.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70621"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454015","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":"Proteostasis Rebalancing by LET-607 Deficiency Promotes Longevity.","authors":"Haixiang Tong, Wei Li, Pangui Yuan, Feng Li, Qin Liu, Shanshan Pang, Haiqing Tang","doi":"10.1111/acel.70620","DOIUrl":"10.1111/acel.70620","url":null,"abstract":"<p><p>Disruption of proteostasis is a hallmark of aging. Given that cellular resources are limited, this necessitates a coordinated orchestration of different proteostatic subsystems. Yet, the principles governing this process, including the potential role of trade-offs, are not well defined. Here, we report a trade-off between the endoplasmic reticulum unfolded protein response (UPR^ER) and the cytosolic UPR (UPR^cyto) in C. elegans that influences lifespan. We find that wild-type animals maintain high UPR^ER activity but low UPR^cyto activity, a balance actively enforced by the transcription factor LET-607 (ortholog of mammalian CREBH). Consequently, LET-607 deficiency releases this trade-off, causing a seesaw-like rebalancing: UPR^ER activity decreases while UPR^cyto increases. Strikingly, this rebalancing contributes to longevity: animals lacking LET-607 exhibited extended lifespan in a UPR^cyto dependent manner. Mechanistically, LET-607 deficiency downregulates one-carbon cycle, which provides the methyl donor S-adenosylmethionine. This subsequently alleviates H3K9me-mediated repression at the promoters of UPR^cyto genes, a process involving the regulators and readers of this histone mark, leading to UPR^cyto activation. Our study reveals a transcriptional mechanism that enforces a proteostatic trade-off and demonstrates that evolutionarily acquired UPR balance in wild-type animals is suboptimal for longevity, supporting the antagonistic pleiotropic theory of aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70620"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13347320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409661","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}