Aging Cell最新文献

{"title":"Muscle Mitochondrial Oxidative Capacity and Cognitive Decline Over up to a Decade: Sex Differences","authors":"Qu Tian,&nbsp;Anjay Ambegaonkar,&nbsp;Luigi Ferrucci","doi":"10.1111/acel.70637","DOIUrl":"https://doi.org/10.1111/acel.70637","url":null,"abstract":"<p>Higher skeletal muscle oxidative capacity is associated with higher cognitive function and preserved brain structure. The relationship between mitochondria and brain health suggests sex differences, but whether the relationship with cognition shows sex differences and underlying mechanisms is unknown. We analyzed the relationships between mitochondrial oxidative capacity and up to 12-year prospective cognitive data in 506 older participants (mean age = 74.4 years, 58% Women) and examined sex differences, using linear mixed-effects models adjusted for demographics. Cognitive composite scores were computed using multiple cognitive measures. Muscle oxidative capacity was assessed as the post-exercise recovery rate of phosphocreatine (kPCr) via phosphorus-31 MR spectroscopy. We tested mediation effects of blood-based clinical markers. Cross-sectionally, higher kPCr was associated with higher cognitive scores (<i>p</i> &lt; 0.001 overall, <i>p</i> = 0.001 men, <i>p</i> = 0.029 women), and there was no significant kPCr-by-sex interaction (<i>p</i> = 0.308). Longitudinally, there was a significant kPCr-by-sex interaction (<i>p</i> = 0.042). The association of higher kPCr with slower cognitive decline was prominent in men (<i>p</i> = 0.077), particularly executive function (<i>p</i> = 0.010) and processing speed (<i>p</i> = 0.049). In men, fasting glucose and hemoglobin A1C mediated both cross-sectional and longitudinal associations between kPCr and cognition (all <i>p</i> &lt; 0.05, 23.1% by glucose). Total protein and globulin also mediated the cross-sectional association in men to a lesser extent (9.5%–9.9%). In women, ESR, hemoglobin, and hematocrit mediated the cross-sectional association (all <i>p</i> &lt; 0.05, 22.7% by hematocrit). Muscle mitochondria are linked to cognition and predict cognitive decline primarily in men. Underlying mechanisms appear to differ by sex, likely through a metabolic-drive pathway in men and a hematologic-inflammatory pathway in women. Omics studies are warranted to elucidate the sex-specific biological processes.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 8","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70637","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148533893","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":"Down-Regulation of TFEB With Defective Autophagy in the Susceptibility of Aging Kidneys to Septic Acute Kidney Injury","authors":"Yu Xiang,&nbsp;Ying Fu,&nbsp;Zhiwen Liu,&nbsp;Yu Han,&nbsp;Wenwen Wu,&nbsp;Juan Cai,&nbsp;Dongshan Zhang,&nbsp;Zheng Dong","doi":"10.1111/acel.70644","DOIUrl":"https://doi.org/10.1111/acel.70644","url":null,"abstract":"<p>Sepsis-associated acute kidney injury (SA-AKI) is a common and devastating disease that has a significantly higher incidence and greater severity in elderly patients, but the molecular basis underlying SA-AKI in the elderly is largely unknown. Recent studies have proved autophagy as an intrinsic protective mechanism against AKI; however, the role and regulation of autophagy in aging kidneys remain unclear. Here we demonstrate that defective autophagy activation in aging kidneys is a key to their susceptibility to SA-AKI. In our experiments, the ability of autophagy activation was impaired in aging kidneys in response to SA-AKI in mice. In vitro, activation of autophagy with TAT-Beclin-1 peptide mitigated lipopolysaccharide (LPS)-induced apoptosis and inflammation in senescent renal proximal tubular cells. Single-cell sequencing revealed significant age-related alterations in autophagy-associated genes in septic AKI, including TFEB. Overexpression of TFEB could partially restore autophagic activity in senescent renal tubular cells and protect them from LPS-induced damage. Moreover, in vivo treatment with the curcumin analog C1 (a TFEB activator) enhanced autophagic function in aging kidneys and reduced LPS-induced AKI. These results demonstrate the defective autophagy activation in aging kidneys, which contributes to the SA-AKI sensitivity and susceptibility in the elderly, suggesting a therapeutic strategy by enhancing autophagy.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 8","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70644","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148533895","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":"Mechanistic Study of Platelet Membrane-Coated Resveratrol Nanosystem in Mitochondrial Dysfunction and Endothelial Senescence During Atherosclerotic Lesion Development via FOXM1 Activation","authors":"Li Xiao,&nbsp;Zexin Zhan,&nbsp;Ping Liu,&nbsp;Bing Qin","doi":"10.1111/acel.70632","DOIUrl":"https://doi.org/10.1111/acel.70632","url":null,"abstract":"<p>Atherosclerosis (AS) is closely linked to endothelial cell (EC) senescence and mitochondrial dysfunction, which impair vascular repair. Resveratrol (RSV) has antioxidant, anti-inflammatory, and pro-angiogenic effects, but its clinical use is restricted by poor bioavailability. This study aimed to construct a platelet membrane-coated resveratrol nanosystem (PM@RSV NPs) and investigate its mechanism of action in delaying the progression of AS by activating FOXM1 to improve mitochondrial function, inhibit EC senescence, and promote vascular regeneration. PM@RSV NPs were prepared using a solvent evaporation method combined with membrane-coating technology, and gene expression profiles and key regulatory networks were analyzed through RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), and least absolute shrinkage and selection operator (LASSO) regression. In vitro, PM@RSV NPs enhanced mitochondrial membrane potential and ATP generation while decreasing ROS accumulation and the number of SA-β-Gal-positive cells, accompanied by FOXM1 upregulation in ECs. In vivo experiments demonstrated that PM@RSV NPs significantly reduced plaque area, improved mitochondrial function, decreased levels of senescence markers, and promoted vascular regeneration via FOXM1 regulation. In addition, PM@RSV NPs preferentially accumulated in ox-LDL-injured MAECs and AS lesion-associated vascular endothelium, mainly through platelet-membrane adhesion proteins such as GPV and P-selectin; their biosafety was evaluated by EC viability/apoptosis assays, histological examination of major organs, and serum biochemical indices of liver and kidney function. This study confirmed that PM@RSV NPs improved mitochondrial function, inhibited endothelial senescence, and enhanced vascular regeneration by activating FOXM1, offering a novel therapeutic strategy for treating AS.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 8","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70632","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148533894","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":"Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights","authors":"Heng Zhang,&nbsp;Guangyu Liang,&nbsp;Anding Liu","doi":"10.1111/acel.70639","DOIUrl":"https://doi.org/10.1111/acel.70639","url":null,"abstract":"<p>During aging, hepatic structural, metabolic, and regulatory impairments collectively contribute to the decline of hepatic and systemic function. As a core hepatic physiological process, ammonia metabolism is essential for maintaining systemic nitrogen homeostasis. However, how ammonia metabolism is altered during aging, and whether these changes contribute to hepatic and systemic decline, remain insufficiently understood. In this review, current evidence linking hepatic ammonia metabolism to liver aging is summarized. The major pathways of hepatic ammonia disposal, including the urea cycle and glutamine synthesis, are first outlined. Age-related changes in these pathways are then discussed, with emphasis on mitochondrial dysfunction, altered post-translational regulation, transcriptional and epigenetic remodeling, and disruption of metabolic zonation. Emerging evidence that ammonia functions not only as a nitrogen waste product but also as a bioactive stress signal is also reviewed. In this context, ammonia has been implicated in mitochondrial injury, senescence-associated signaling, proteostasis defects, and inflammatory and fibrogenic remodeling. The systemic consequences of ammonia dysregulation are further considered, particularly along the liver–brain, liver–muscle, and liver–gut axes. Finally, current and emerging therapeutic strategies are evaluated, including ammonia-lowering agents, senotherapeutics, and microbiota-directed approaches. Collectively, this review identify ammonia metabolism as an underappreciated but potentially axis for understanding liver aging, thereby providing a framework for future mechanistic and translational studies.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 8","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70639","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148533896","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":"The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging","authors":"Aino Heikkinen,&nbsp;Liina Uusitalo-Kylmälä,&nbsp;Ida Blom,&nbsp;Jørn Wulff Helge,&nbsp;Linn Gillberg,&nbsp;Robert Seaborne,&nbsp;Steen Larsen,&nbsp;Macsue Jacques,&nbsp;Robin Grolaux,&nbsp;Sari Aaltonen,&nbsp;Jaakko Kaprio,&nbsp;Birgitta W. van der Kolk,&nbsp;Sini Heinonen,&nbsp;Nir Eynon,&nbsp;Kirsi H. Pietiläinen,&nbsp;Riikka Kivelä,&nbsp;Eija Pirinen,&nbsp;Miina Ollikainen","doi":"10.1111/acel.70638","DOIUrl":"https://doi.org/10.1111/acel.70638","url":null,"abstract":"<p>Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD⁺, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementation and 4–6 weeks HIIT on epigenetic age acceleration (EAA, via seven epigenetic clocks) in human skeletal muscle across three independent studies. NR supplementation was associated with reduced muscle EAA, particularly when measured with the PCHannum, MEAT, and DunedinPACE clocks, while HIIT produced opposite effects in some clocks, notably increasing pace of aging by DunedinPACE. Correlation analyses revealed that changes in skeletal muscle mitochondrial content correlated with changes in MEAT-derived EAA after NR and 6 weeks of HIIT. Together, these findings indicate that skeletal muscle epigenetic aging can be modulated by NR and HIIT interventions but in opposing directions, highlighting a potential link between mitochondrial abundance and epigenetic clocks. Further studies are warranted to clarify how NR and exercise regulate epigenetic aging. These results offer new insights into development of strategies for promoting epigenetic outcomes and healthy aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 8","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70638","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148533892","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":"Interplay of the ENS and Microbiota With Murine Gut Epithelium-Derived Organoids in Aging","authors":"Tinh Thi Nguyen,&nbsp;Dennis Schapelhouman,&nbsp;Katharina Fischer,&nbsp;Jia-Xuan Chen,&nbsp;Mario Dejung,&nbsp;Fridolin Kielisch,&nbsp;Julia Varga,&nbsp;Johannes Piepgras,&nbsp;Matthew Ahn,&nbsp;Oliver Tüscher,&nbsp;Peter Baumann,&nbsp;Sandra Schick,&nbsp;Kristina Endres","doi":"10.1111/acel.70608","DOIUrl":"10.1111/acel.70608","url":null,"abstract":"<p>The intestine is one of the first organs to show signs of aging, including cellular changes, microbiota shifts, and reduced regenerative capacity. The different components of the gut—such as the epithelium (which is directly exposed to a diverse array of host–microbe interactions), the microbiota itself, and the underlying enteric nervous system—likely contribute to aging in distinct ways. Understanding their individual and interactive roles is key to elucidating the mechanisms of intestinal aging. To better understand the contribution of individual components to intestinal aging, we analyzed gut tissue characteristics and compared these parameters with the composition and gene expression levels of colonic organoids by using two mouse strains: the aging-resistant SAMR1 line and the SAMP8 line, which exhibit an accelerated aging phenotype. Here, we demonstrate that colonic organoids derived from these mice retain the age-related characteristics of the colonic tissue, including changes in morphology and cellular composition. Furthermore, introducing the enteric nervous system into organoid culture revealed that the age of the epithelium exerts a more pronounced influence on the aging phenotype than the age of the innervating tissue. Interestingly, successfully delivering fecal extracts to organoids revealed that gut microbiota metabolites from aged animals resulted in an aging phenotype of the gut epithelium in vitro. In summary, our findings indicate the impact of aging on the gut epithelium and its interplay with the nervous system and microbiota. This may in future provide new strategies for slowing the aging process in the gut by manipulating the gut commensals.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 7","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70608","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374036","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":"Correction to “Telomerase Knockout in Myeloid Cells Predisposes Mice to Foam Cell Formation, Dyslipidemia, Lung Fibrosis, and Cardiac Dysfunction”","authors":"","doi":"10.1111/acel.70619","DOIUrl":"10.1111/acel.70619","url":null,"abstract":"<p>Gao, Z., Y. Yu, D. Wiggins, E. M. Sevick-Muraca, and M. G. Kolonin. 2026. “Telomerase Knockout in Myeloid Cells Predisposes Mice to Foam Cell Formation, Dyslipidemia, Lung Fibrosis, and Cardiac Dysfunction.” <i>Aging Cell</i> 25: e70490. https://doi.org/10.1111/acel.70490.</p><p>We apologize for this error.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 7","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70619","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366256","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":"Age-Associated Senescence of Decidual Macrophages: A Key Mediator of Adverse Pregnancy Outcomes in Advanced Maternal Age","authors":"Yujing Zhang,&nbsp;Yiming Zhang,&nbsp;Guangshun Gong,&nbsp;Zhijing Li,&nbsp;Wenjing Xiong,&nbsp;Xuhui Fang,&nbsp;Ning Lu,&nbsp;Di Wang,&nbsp;Yihui Li,&nbsp;Aihua Liao","doi":"10.1111/acel.70614","DOIUrl":"10.1111/acel.70614","url":null,"abstract":"<p>Senescence of immune cells can drive senescence of solid organs, and reversing immune cell senescence ameliorates organismal senescence phenotypes. As the second largest subset of decidual immune cells, macrophages play a critical role in pregnancy. However, whether decidual macrophages (DM) exhibit senescence in advanced maternal age (AMA) pregnancies (≥ 35 years old) and their involvement in AMA-related adverse outcomes remain undefined. This study elucidates the phenotypic and functional characteristics of DM in AMA pregnancies through clinical samples, animal models, and in vitro experiments. It clarifies the mechanisms underlying DM aging and explores novel intervention strategies to reverse DM aging and improve pregnancy outcomes in AMA pregnancies. We found that the presence of DM senescence in AMA pregnancies, manifested by an increased proportion of the pro-inflammatory phenotype M1, increased expression of senescence markers (P53 and SA-β-Gal), and decreased phagocytic capacity—all associated with the development of adverse outcomes in AMA. The mechanistic basis of DM senescence involves two key pathways: on the one hand, low expression of forkhead box O3 causes DM senescence by downregulating mitophagy. On the other hand, elevated IL-6 in the uterine microenvironment exacerbates senescence. Adoptive transfer of young mouse bone marrow-derived macrophages significantly rescues embryo resorption rates and placental development in AMA pregnant mice. Overall, our study uncovers novel mechanisms and therapeutic strategies for AMA-related adverse pregnancy outcomes through a new perspective of uterine macrophage senescence, providing new intervention ideas to improve adverse pregnancy outcomes in AMA.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 7","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70614","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366183","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 Gut-Centric View of Ageing: A Pilot Analysis Mapping Age-Associated Immune and Molecular Alterations in Colonic Mucosa Using Spatial Proteomics","authors":"Jack Sullivan,&nbsp;Jessica Conway,&nbsp;Sophie J. Hopkin,&nbsp;Myriam Chimen,&nbsp;Niharika A. Duggal","doi":"10.1111/acel.70605","DOIUrl":"10.1111/acel.70605","url":null,"abstract":"<p>Investigating age-associated changes in intestine and understanding immune-related intestinal dysfunctions is essential for promoting healthy ageing. Mucosal surfaces represent a distinct immune compartment enriched with specialised lymphocytes that interact dynamically with the epithelial layer. In this study, we present novel spatially resolved insights into the cellular and molecular alterations in the ageing murine gut mucosa. Our findings reveal a complex network of interdependent age-related changes, including accumulation of senescent T cells near the epithelial layer, increased expression of ribosomal protein S6 kinase (mTOR target), upregulation of glycolytic enzyme (GAPDH) linked with metabolic reprogramming and elevated apoptosis activity (caspase 3). Together, these molecular signatures point to a progressive dysregulation of mucosal immune homeostasis highlighting reduced tissue resilience as we age. Furthermore, our assessment revealing increased gut-homing of aged naïve human T cells towards the mucosa suggests that exposure to antigenic stimulation at the mucosa is driving this senescence state. Although further investigations are needed to elucidate the causal mechanisms. Our findings highlight the therapeutic potential of pharmacological drugs (e.g., metformin, senolytics) and lifestyle-based approaches (such as caloric restriction) targeting key pathways reported to modulate the immune-epithelial interactions and support intestinal homeostasis during ageing.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 7","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70605","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349930","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":"Clonal Analyses Reveal the Impact of Hematopoietic Stem and Progenitor Cell Aging on T Cell Development","authors":"Julia Gensheimer,&nbsp;Jessica LaGosh,&nbsp;Emma R. Moulton,&nbsp;Victoria Sun,&nbsp;Stephanie C. de Barros,&nbsp;Encarnacion Montecino-Rodriguez,&nbsp;Gloria Yiu,&nbsp;Xuegang Yuan,&nbsp;Kenneth Dorshkind,&nbsp;Gay M. Crooks","doi":"10.1111/acel.70615","DOIUrl":"10.1111/acel.70615","url":null,"abstract":"<p>T cell output from the thymus falls throughout life and is associated with profound remodeling of the thymic stroma. To what extent the decline in T cell output is caused by aging of the hematopoietic stem and progenitor cells (HSPCs) has been difficult to define because of HSPC heterogeneity, the multi-stage process of HSPC migration, and the cross-talk between hematopoietic and stromal elements of the thymus. To address the contribution of HSPC aging on T cell development, we interrogated T cell differentiation of phenotypically defined HSPCs from young and aged bone marrow using the Artificial Thymic Organoid (ATO) system, an in vitro model which allows quantification of T cell differentiation from single HSPCs within a controlled microenvironment. Phenotypically, most HSCs from young bone marrow were CD150^lo lymphoid-biased (Ly-HSC), whereas aged HSCs were predominantly CD150^hi myeloid-biased (My-HSC). Clonal analysis showed Ly-HSCs had greater T cell potential than My-HSCs, but aging had little if any impact on T cell output from the same immunophenotypic HSC. Further, clonal studies of early thymic progenitors (ETPs) demonstrated comparable T cell potential in young and aged cells. We conclude that the hematopoietic contribution to thymic insufficiency during aging is likely due to a relative shift in the aged bone marrow to myeloid-biased HSCs, rather than a per cell loss of T cell potential across HSPC in general. The profound changes that occur in the thymic microenvironment during aging likely also provide a major contribution to defects in thymopoiesis.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 7","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70615","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350018","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}