Aging Cell最新文献

{"title":"Organ Specificity and Commonality of Epigenetic Aging in Low- and High-Running Capacity Rats","authors":"Takuji Kawamura,&nbsp;Csaba Kerepesi,&nbsp;Juliet Polok Sarkar,&nbsp;Ferenc Torma,&nbsp;Zoltan Bori,&nbsp;Lei Zhou,&nbsp;Peter Bakonyi,&nbsp;Attila Kolonics,&nbsp;Laszlo Balogh,&nbsp;Mitsuru Higuchi,&nbsp;Vivien Pillár,&nbsp;Karolina Pircs,&nbsp;Lauren Gerard Koch,&nbsp;Steven Loyal Britton,&nbsp;Erika Koltai,&nbsp;Zsolt Radak","doi":"10.1111/acel.70110","DOIUrl":"10.1111/acel.70110","url":null,"abstract":"<p>Epigenetic drift, which is gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging, and the molecular mechanisms underlying their interactions are poorly understood. Here, we investigated the relationship between cardiorespiratory fitness (CRF), epigenetic aging, and promoter methylation of individual genes across multiple organs in selectively bred low- and high-capacity runner (LCR and HCR) aged rats. Epigenetic clocks, trained on available rat blood-derived reduced representation bisulfite sequencing data, did not reflect differences in CRF between LCR and HCR rats across all four organs. However, we observed organ-specific differences in global mean DNA methylation and mean methylation entropy between LCR and HCR rats, and the direction of these differences was the opposite compared to the age-related changes in the rat blood. Notably, the soleus muscle exhibited the most pronounced differences in promoter methylation due to CRF. We also identified seven genes whose promoter methylation was consistently influenced by CRF in all four organs. Moreover, we found that age acceleration of the soleus muscle was significantly higher compared to the heart and the hippocampus, and significantly lower compared to the large intestine. Finally, we found that the age acceleration was not consistent across organs. Our data suggest that CRF associates with epigenetic aging in an organ-specific and organ-common manner. Our findings provide important insights into the biology of aging and emphasize the need to validate rejuvenation strategies in the context of the organ-specific nature of epigenetic aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245420","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":"Type-Specific Single-Neuron Analysis Reveals Mitochondrial DNA Maintenance Failure Affecting Atrophying Pontine Neurons Differentially in Lewy Body Dementia Syndromes","authors":"Eloise J. Stephenson,&nbsp;Laura J. Bailey,&nbsp;Stephen Gentleman,&nbsp;Helen Tuppen,&nbsp;Istvan Bodi,&nbsp;Claire Troakes,&nbsp;Christopher M. Morris,&nbsp;Tony M. Carr,&nbsp;Sarah Guthrie,&nbsp;Joanna L. Elson,&nbsp;Ilse S. Pienaar","doi":"10.1111/acel.70125","DOIUrl":"10.1111/acel.70125","url":null,"abstract":"<p>The age-associated neurodegenerative disorder, Lewy body dementia (LBD), encompasses neuropsychiatric symptom-overlapping Dementia with Lewy bodies (DLB) and Parkinson's Disease with Dementia (PDD). We characterised how differential mitochondrial DNA (mtDNA) profiles contribute to neurotype-specific neurodegeneration and thereby clinicopathological heterogeneity, between LBD's syndromes. We further characterised key nuclear-encoding genes' recalibrations in response to such mtDNA changes. In post-mortem ‘single-cell’ acetylcholine- and noradrenaline-producing neurons, respectively of the pedunculopontine nucleus (PPN) and locus coeruleus (LC) from DLB, PDD and neurological-control brains, we quantified ‘major arc’-locating mtDNA deletions (mtDels) and -copy number (mtCN), and measured mRNA levels of nuclear-encoding genes regulating mtDNA maintenance, -biogenesis and mitophagy. DLB cases' OXPHOS defect instigating mtDel burden was higher in both neurotypes than PDD. In DLB, mtCN was reduced for both neurotypes, but PDD cases revealed mtDNA depletion in LC-noradrenergic neurons only. DLB patients' shorter survival correlated with PPN-cholinergic neurons' mtDel levels, inversely with wild-type mtCN, implying that such neurons' inability to maintain sufficient wild-type mtDNA content drive DLBs' rapid psycho-cognitive manifestations. Contrastingly, PDD's longer disease duration allowed compensation against mtDels' clonal expansion in PPN-cholinergic neurons. Moreover, PDD induced mRNA depletion of a mitochondrial genome maintenance gene in PPN-cholinergic neurons, whilst LC-noradrenergic neurons displayed reduced expression of a mitophagy regulating gene. Here we identify mitochondrial genome maintenance and mitophagy pathway enrichment as therapeutic targets to offset defective mtDNA within pontine cholinergic and noradrenergic neurons of PDD patients. The pronounced LBD subtype-related mitochondria-nuclear genetic differences question the consensus that pathology converges at disease end-stage, calling for LBD subtype and neurotype-specific therapeutics.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70125","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232776","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 Novel GH Deficient Rat Model Reveals Cross-Species Insights Into Aging","authors":"Soe Maung Maung Phone Myint,&nbsp;Alexander Tate Lasher,&nbsp;Kaimao Liu,&nbsp;Aron M. Geurts,&nbsp;Steven N. Austad,&nbsp;Liou Y. Sun","doi":"10.1111/acel.70126","DOIUrl":"10.1111/acel.70126","url":null,"abstract":"<p>Multiple studies in mice with genetically disrupted growth hormone (GH) signaling have demonstrated that such disruption results in reduced body size, robustly increased longevity (&gt; 50% in some cases), and improvements across multiple health parameters. However, it remains unclear how generalizable these findings are across mammals. Evidence in rats is limited and inconsistent. These conflicting results highlight the need for further investigation into the role of GH signaling in longevity across species. To address this gap, we developed a novel GH-deficient rat model using CRISPR/Cas9 technology to introduce a 10 bp deletion in exon 3 of the gene encoding rat GH-releasing hormone (GHRH) yielding a non-functional GHRH product. Physiological characterization of GHRH knockout (KO) rats revealed that they were half the body weight of wild-type controls. Additionally, relative to controls, they displayed an increased percent body fat, enhanced insulin sensitivity, reduced circulating insulin-like growth factor I (IGF-I) concentration, and a decreased reliance on glucose oxidation for energy metabolism, as determined by indirect calorimetry. Analysis of the gut microbial community in adult GHRH-KO rats further revealed a less diverse male microbiome, but a more diverse female KO microbiome compared to controls. Collectively, these findings demonstrate that multiple aspects of the GH activity-deficient phenotype, well-documented in mice, are faithfully recapitulated in our rat model. Therefore, the GHRH-deficient rat model represents a valuable new tool for advancing our understanding of the role of GH signaling in aging processes.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232775","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":"Cross-Analysis of Single-Cell Transcriptomic Datasets Reveals Conserved Neurogenic Gene Signatures and New Insights Into Neural Stem Cell Aging","authors":"Oliver Polzer,&nbsp;E. Kinloch,&nbsp;P. J. Lucassen,&nbsp;E. Salta,&nbsp;C. P. Fitzsimons","doi":"10.1111/acel.70106","DOIUrl":"10.1111/acel.70106","url":null,"abstract":"<p>Hippocampal adult neural stem cells (NSCs) contribute to neurogenesis and astrogliogenesis throughout life. They play multifaceted roles in hippocampal function, including memory processing, stress regulation, and cognitive flexibility. Located in unique neurogenic niches like the subgranular zone of the hippocampal dentate gyrus, NSCs exhibit notable heterogeneity and can be classified into quiescent, activated, and intermediate transitioning states. This diversity, while instrumental to their adaptability and function, presents challenges in molecular classification and functional interrogation. Here, we discuss current limitations and compare NSC transcriptional profiles from publicly available single-cell RNA sequencing datasets. We address discrepancies in NSC classification between studies, identify conserved gene expression profiles, and propose new markers that could serve as standardized references. Furthermore, we explore how pseudotime inference analyses provide insights into the temporal dynamics of NSCs and their progression toward neural progenitors, further aiming to optimize their classification. We also examine cellular changes in NSCs during aging and explore the potential of these cells to undergo senescence. Our work helps to resolve inconsistencies in current cell-type annotations in literature and proposes a framework to study and classify the different states of NSCs, thereby offering a better understanding of their dynamic roles in neurogenesis, aging, and cellular senescence.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214457","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 “Disease Aggravation With Age in an Experimental Model of Multiple Sclerosis: Role of Immunosenescence”","authors":"","doi":"10.1111/acel.70129","DOIUrl":"10.1111/acel.70129","url":null,"abstract":"<p>Dema M, Eixarch H, Hervera A, Castillo M, Villar LM, Montalban X, Espejo C. <i>Aging Cell</i>. 2025 May;24(5):e14491. https://doi.org/10.1111/acel.14491. PMID: 39894902.</p><p>In the Acknowledgments section, the following acknowledgment was inadvertently omitted from the final version:</p><p>“We would also like to thank Cristina Tuñí and Flomics Biotech for their support in carrying out the RNA-Seq study.”</p><p>The corrected acknowledgment would be:</p><p>We thank Xavier Vidal and the Statistics and Bioinformatics Unit (UEB) at Vall d'Hebron Hospital Research Institute (VHIR) for their support in carrying out the statistical analysis. We would also like to thank the Biologia-Bellvitge Unit from Scientific and Technological Centers (CCiTUB), Universitat de Barcelona, and staff Beatriz Barroso and Esther Castaño for their support and advice on UMAP representations. Finally, we would also like to thank Cristina Tuñí and Flomics Biotech for their support in carrying out the RNA-Seq study.</p><p>We apologize for this error.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 7","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207248","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":"Nicotinamide Riboside Supplementation Benefits in Patients With Werner Syndrome: A Double-Blind Randomized Crossover Placebo-Controlled Trial","authors":"Mayumi Shoji,&nbsp;Hisaya Kato,&nbsp;Masaya Koshizaka,&nbsp;Hiyori Kaneko,&nbsp;Yusuke Baba,&nbsp;Takahiro Ishikawa,&nbsp;Naoya Teramoto,&nbsp;Daisuke Kinoshita,&nbsp;Ayano Yamaguchi,&nbsp;Yukari Maeda,&nbsp;Yosuke Inaba,&nbsp;Yuki Shiko,&nbsp;Yoshihito Ozawa,&nbsp;Vilhelm A. Bohr,&nbsp;Yoshiro Maezawa,&nbsp;Koutaro Yokote","doi":"10.1111/acel.70093","DOIUrl":"10.1111/acel.70093","url":null,"abstract":"<p>Werner syndrome (WS) is a rare hereditary progeroid syndrome caused by mutations in the <i>WRN</i> gene. Patients frequently develop various age-associated diseases prematurely, often leading to early mortality (≤ 60 years of age). Depletion of nicotinamide adenine dinucleotide (NAD)⁺ has been reported in patients with WS, suggesting a key role in the pathogenesis of WS. NAD⁺ supplementation may improve the condition of WS and other accelerated aging diseases. Therefore, we conducted a double-blind, randomized, crossover, placebo-controlled trial in patients with WS to evaluate the safety and efficacy of the NAD⁺ precursor, nicotinamide riboside (NR). NR (1000 mg) or placebo capsules were self-administered once daily for 26 weeks, followed by a crossover to the opposite arm for another 26 weeks. The primary endpoint was the safety of NR. Secondary endpoints included NAD⁺ levels in plasma, number, and size of skin ulcers, blood examinations, sarcopenia, heel pad thickness, cardio–ankle vascular index (CAVI), and ankle–brachial index. The exploratory endpoints involved metabolome profiles of plasma. No serious adverse events were observed during NR treatment. Importantly, CAVI improved, the skin ulcer area decreased, and heel pad thinning showed a declining trend. Metabolomic analysis revealed a significant decrease in blood creatinine. NR treatment significantly improved arterial stiffness, as indicated by CAVI, and likely suppressed renal functional decline in patients with WS. Therefore, NR may be beneficial for preventing atherosclerosis, skin ulcers, and kidney dysfunction in patients with WS.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214458","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 Comprehensive Multiomics Signature of Doxorubicin-Induced Cellular Senescence in the Postmenopausal Human Ovary","authors":"Pooja Raj Devrukhkar,&nbsp;Mark A. Watson,&nbsp;Bikem Soygur,&nbsp;Fei Wu,&nbsp;Joanna Bons,&nbsp;Hannah Anvari,&nbsp;Tomiris Atazhanova,&nbsp;Nicolas Martin,&nbsp;Tommy Tran,&nbsp;Kevin Schneider,&nbsp;Jacob P. Rose,&nbsp;Daniel Winer,&nbsp;Elisheva Shanes,&nbsp;Mary Ellen G. Pavone,&nbsp;Judith Campisi,&nbsp;David Furman,&nbsp;Simon Melov,&nbsp;Birgit Schilling,&nbsp;Francesca E. Duncan","doi":"10.1111/acel.70111","DOIUrl":"10.1111/acel.70111","url":null,"abstract":"<p>A major aging hallmark is the accumulation of cellular senescence burden. Over time, senescent cells contribute to tissue deterioration through chronic inflammation and fibrosis driven by the senescence-associated secretory phenotype (SASP). The human ovary is one of the first organs to age, and prominent age-related fibroinflammation within the ovarian microenvironment is consistent with the presence of senescent cells, but these cells have not been characterized in the human ovary. We thus established a doxorubicin-induced model of cellular senescence to establish a “senotype” (gene/protein signature of a senescence cell state) for ovarian senescent cells. Explants of human postmenopausal ovarian cortex and medulla were treated with doxorubicin for 24 h, followed by culture for up to 10 days in a doxorubicin-free medium. Tissue viability was confirmed by histology, lack of apoptosis, and continued glucose consumption by explants. Single nuclei sequencing and proteomics revealed an unbiased signature of ovarian senescence. We identified distinct senescence profiles for the cortex and medulla, driven predominantly by epithelial and stromal cells. Proteomics uncovered subregional differences in addition to 120 proteins common to the cortex and medulla SASP. Integration of transcriptomic and proteomic analyses revealed 26 shared markers, defining a senotype of doxorubicin-induced senescence unique to the postmenopausal ovary. A subset of these proteins: Lumican, SOD2, MYH9, and Periostin were mapped onto native tissue to reveal compartment-specific localization. This senotype will help determine the role of cellular senescence in ovarian aging, inform biomarker development to identify, and therapeutic applications to slow or reverse ovarian aging, senescence, and cancer.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197833","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":"Biomarkers of Cellular Senescence in Type 2 Diabetes Mellitus","authors":"Caroline Hoong,&nbsp;Joshua N. Farr,&nbsp;David G. Monroe,&nbsp;Thomas A. White,&nbsp;Elizabeth J. Atkinson,&nbsp;Amanda Tweed,&nbsp;Allyson K. Palmer,&nbsp;Nathan K. LeBrasseur,&nbsp;Jad G. Sfeir,&nbsp;Sundeep Khosla","doi":"10.1111/acel.70120","DOIUrl":"10.1111/acel.70120","url":null,"abstract":"<p>Although animal studies have linked cellular senescence to the pathogenesis and complications of type 2 diabetes mellitus (T2DM), there is a paucity of corroborating data in humans. Thus, we measured a previously validated marker for senescent cell burden in humans, T-cell expression of <i>p16</i> mRNA, along with additional biomarkers, to compare the senescence phenotypes of postmenopausal control (lean, <i>N</i> = 37) and T2DM (<i>N</i> = 27) participants. To control for effects of obesity alone, we included a third group of obese but non-diabetic women (<i>N</i> = 29) who were matched for body mass index to the T2DM participants. In addition, given the increase in fracture risk in T2DM despite preserved or even increased bone mineral density, we related these senescence biomarkers in the T2DM participants to skeletal microarchitectural parameters. Relative to the lean participants, T-cell <i>p16</i> and <i>p21</i>^<i>Cip1</i> expression was increased in the T2DM, but not the obese, non-diabetic participants. Expression of <i>p16</i> and <i>p21</i>^<i>Cip1</i> was positively associated with HbA1c and an index of skin advanced glycation end-products. T2DM was also associated with an increase in a number of SASP factors. Among participants with T2DM, women in the highest tertile for T-cell expression of <i>p16</i> had significantly reduced tibial cortical area and thickness as compared to those in the lower two tertiles. Overall, our studies link cellular senescence to metabolic and skeletal alterations in T2DM and point to the need for further studies evaluating the role of cellular senescence in mediating skeletal fragility, as well as potentially other complications in T2DM.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191298","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":"Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches","authors":"Kevin O. Murray,&nbsp;Sophia A. Mahoney,&nbsp;Katelyn R. Ludwig,&nbsp;Jill H. Miyamoto-Ditmon,&nbsp;Nicholas S. VanDongen,&nbsp;Nirad Banskota,&nbsp;Allison B. Herman,&nbsp;Douglas R. Seals,&nbsp;Robert T. Mankowski,&nbsp;Matthew J. Rossman,&nbsp;Zachary S. Clayton","doi":"10.1111/acel.70114","DOIUrl":"10.1111/acel.70114","url":null,"abstract":"<p>Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on—2 weeks off—1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice. The improvements in frailty and grip strength in old mice were accompanied by favorable modulation of the skeletal muscle transcriptome, including lower abundance of cellular senescence-related genes (e.g., <i>Cdkn1a</i> and <i>Ddit4</i>). Improvements in frailty and grip strength with fisetin were comparable to those observed with genetic-based clearance of excess p16+ senescent cells and treatment with ABT-263. Taken together, our findings provide proof-of-concept support for fisetin as a senolytic strategy to improve physical function with aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172212","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":"Circadian Gene BMAL1 Regulation of Cellular Senescence in Thyroid Aging","authors":"Dandan Zong,&nbsp;Baihui Sun,&nbsp;Qiting Ye,&nbsp;Hongxin Cao,&nbsp;Haixia Guan","doi":"10.1111/acel.70119","DOIUrl":"10.1111/acel.70119","url":null,"abstract":"<p>As global aging accelerates, the incidence of thyroid diseases, particularly hypothyroidism, is rising in the elderly. The thyroid-stimulating hormone (TSH) levels increase in healthy elderly populations. However, whether the thyroid undergoes cellular senescence and how this relates to thyroid hormone (TH) synthesis remain unclear. To investigate the molecular and functional characteristics of thyroid aging, we performed scRNA-seq on human thyroids from young, middle-aged, and old groups, identifying thousands of aging-related differentially expressed genes and revealing the early onset of aging in the middle-aged group. As aging progresses, the expression levels of genes related to TH synthesis increase, suggesting that epithelial cells (EPI) adjust their gene expression in response to elevated TSH levels. Additionally, the senescence-associated secretory phenotype (SASP) in EPI cells is progressively enhanced with aging. We identified a subgroup of epithelial cells (CDKN1A_EPI) characterized by reduced functionality and significantly elevated levels of cellular senescence. We found that the core circadian rhythm gene <i>BMAL1</i> (<i>ARNTL</i>) is downregulated during aging. We further validated this finding using the thyroid-specific <i>Bmal1</i> knockout mouse model, showing that the downregulation of <i>Bmal1</i> inhibits the expression of <i>Nfkbia</i> (<i>NF-κB inhibitor alpha</i>), thereby accelerating cellular senescence and impairing hormone synthesis. Finally, through cell line experiments and transcriptome sequencing, we confirmed that <i>BMAL1</i> knockout leads to decreased <i>NFKBIA</i> expression, promoting thyroid cellular senescence. Our study demonstrates that circadian rhythm disruption accelerates cellular senescence in the thyroid and exacerbates the decline of thyroid function, providing a novel theoretical foundation for understanding thyroid aging mechanisms and maintaining thyroid function stability.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70119","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155352","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}