Aging Cell最新文献

{"title":"Senescence Alters Antimicrobial Peptide Expression and Induces Amyloid-β Production in Retinal Pigment Epithelial Cells","authors":"Jian Liu,&nbsp;Caijiao Yi,&nbsp;Jinyan Qi,&nbsp;Xuexue Cui,&nbsp;Xiangling Yuan,&nbsp;Wen Deng,&nbsp;Mei Chen,&nbsp;Heping Xu","doi":"10.1111/acel.70161","DOIUrl":"10.1111/acel.70161","url":null,"abstract":"<p>Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including <i>APP</i>, <i>RARRES2</i>, <i>FAM3A</i>, <i>HAMP</i>, <i>CAMP</i>, <i>GNLY</i>, and <i>PI3</i>. Senescent RPE cells expressed lower levels of <i>APP</i> and <i>RARRES2</i> mRNA, accompanied by increased intracellular retention of <i>E. coli</i> in a bactericidal assay. Silencing <i>APP</i>, not <i>RARRES2</i>, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (<i>BACE1</i>) and γ-secretase (<i>PS1</i>), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 9","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625090","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 Transcriptome Trajectory Reveals Sex- and Age-Dependent Changes in the Mouse Adrenal Gland","authors":"Hui Wang,&nbsp;Ben Maggard,&nbsp;Huifei Sophia Zheng,&nbsp;Yuan Kang,&nbsp;Chen-Che Jeff Huang","doi":"10.1111/acel.70169","DOIUrl":"10.1111/acel.70169","url":null,"abstract":"<p>In both humans and mice, the adrenal gland is a sexually dimorphic organ, but the extent of this diversity throughout development remains unclear. Here, we analyzed the mouse adrenal gland transcriptome at postnatal days 0, 7, 15, 21, 28, 35, and 49 to uncover its transcriptomic trajectory. Sex-dependent differences, indicated by the number of differentially expressed genes, gradually increase over time. Two Y-linked genes are consistently expressed in male adrenal glands, suggesting that factors beyond sex hormones may contribute to adrenal sexual dimorphism. Genes involved in steroidogenesis, cholesterol synthesis, and catecholamine synthesis exhibit sex- and age-dependent differential expression. Weighted gene co-expression network analysis (WGCNA) identified many genes with known zone-specific adrenal expression, including <i>Akr1c18</i>, <i>Pik3c2g</i>, <i>Cyp2f2</i>, <i>Dhcr24</i>, <i>Thrb</i>, and <i>Spp1</i>, clustering within the same module. FRZB, a WNT inhibitor, was also part of this module, exhibiting sex- and age-dependent expression. Immunostaining confirmed that FRZB is specifically expressed in the inner cortex, aligning with other inner cortex markers. Additionally, heatmap analysis revealed that many WNT downstream genes show age-dependent increases in expression in males, corresponding to progressively lower <i>Frzb</i> levels, suggesting a regulatory role for <i>Frzb</i> in adrenal sexual dimorphism. Furthermore, collagen-related genes were highlighted in the clustered heatmap of all differentially expressed genes due to their gradual decrease in expression over time. These observations suggest that this comprehensive dataset not only enhances our understanding of adrenal development and sexual dimorphism, aids in identifying novel marker genes for specific adrenal cell types, but also holds potential for contributing to aging research.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615581","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":"L-Tryptophan Produced by Bifidobacterium pseudocatenulatum NCU-08 Delays Aging in SAMP8 Mice by Activating the Sirt1/P53/P21/Rb Signaling Pathway","authors":"Tangchang Xu,&nbsp;Xiaoyun Wu,&nbsp;Yifei Zhang,&nbsp;Yujie Cai,&nbsp;Xinfeng Zhang,&nbsp;Qingwei Zeng,&nbsp;Jie Luo,&nbsp;Jing Wei,&nbsp;Tingtao Chen","doi":"10.1111/acel.70166","DOIUrl":"10.1111/acel.70166","url":null,"abstract":"<p>Gut microbiota delays aging by regulating the immune, metabolic, and neurological functions of the host. However, current research on novel probiotics with antiaging properties significantly lags, impacting their application in clinical treatments. In this study, metagenomics, culturomics, and probiotic property screening were used to identify <i>Bifidobacterium pseudocatenulatum</i> NCU-08 as a potential probiotic with anti-aging properties. In addition, <i>B. pseudocatenulatum</i> NCU-08 effectively improved the behavioral characteristics, significantly reduced the levels of the age-related protein β-galactosidase (β-gal) (BP: M = 0.81 vs. 1.13, <i>p</i> &lt; 0.05), attenuated neuronal damage in the hippocampus, and improved the composition of the gut microbiota of senescence-accelerated mouse tendency-8 (SAMP8) mice. The targeted metabolomics suggested that L-tryptophan (L-Trp) may be a key substance for <i>B. pseudocatenulatum</i> NCU-08 to exert anti-aging effects (BP: M = 14878.6 ng/mL vs. 5464.99 ng/mL, <i>p</i> &lt; 0.01). Mechanistically, using the aging model of SAMP8 mice and HT22 mouse hippocampal neuronal cells, it was found that <i>B. pseudocatenulatum</i> NCU-08 might enter the intestine to regulate L-Trp, and then transport it to the brain. In the brain, L-Trp was metabolized to NAD⁺, which activated the Sirt1/P53/P21/Rb signaling pathway, thereby exerting antiaging effects. Interestingly, this antiaging effect was inhibited after the intervention of the Sirt1 inhibitor EX-527. This study is the first to confirm the antiaging properties of NCU-08 isolated from the fecal samples of seven centenarians in Jiangxi Province, providing data support for the future development of probiotic preparations with antiaging effects.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 9","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606929","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":"Transcriptional Diversity in Response to Aging Across Skeletal Muscles","authors":"Can Liu,&nbsp;Dongbin Zheng,&nbsp;Rui Zhang,&nbsp;Hong Li,&nbsp;Xingyan Tong,&nbsp;Yujie Wu,&nbsp;Geng Zhang,&nbsp;Siyuan Wang,&nbsp;Hongyu Chen,&nbsp;Zhinong Ren,&nbsp;Ying Sun,&nbsp;Chengdong Wang,&nbsp;Desheng Li,&nbsp;Xuewei Li,&nbsp;Mingzhou Li,&nbsp;Long Jin","doi":"10.1111/acel.70164","DOIUrl":"10.1111/acel.70164","url":null,"abstract":"<p>Aging leads to a gradual decline in muscle function, yet the mechanisms by which different skeletal muscles respond to aging remain unclear. Here, we constructed transcriptional maps of 11 skeletal muscles with extensive transcriptional diversity from young and old mice. Age-related changes in gene expression displayed distinct tissue-specific patterns, involving muscle diseases and metabolic processes. Notably, the mitochondrial-enriched soleus muscle exhibited superior resistance to aging compared to other skeletal muscles. Further, we generated a single-nuclei transcriptomic atlas on representative skeletal muscles, analyzing 73,170 nuclei. We found the age-related changes in the cellular composition of different skeletal muscles and the emergence of new cell states in aged mice. Among different types of myonuclei, type II myonuclei showed particular sensitivity to aging, with reduced metabolic activity of IIb myonuclei with age. We also found cell-specific changes occurring across nonmuscle nuclei populations, including adipocytes, fibro-adipogenic progenitors, and immune cells, accelerating muscle aging and associated pathologies. Intercellular communication analysis revealed more intensive intercellular interactions in aged skeletal muscles, particularly between myonuclei and other cell types. Specifically, we validated the regulatory role of the EGF/EGFR axis in age-related inflammatory processes. These findings provide insight into muscle biology and aging and highlight potential therapeutic targets for age-associated muscle disorders.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 9","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590094","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":"RETRACTION: Aggravation of Alzheimer's Disease due to the COX-2-Mediated Reciprocal Regulation of IL-1β and Aβ Between Glial and Neuron Cells","authors":"","doi":"10.1111/acel.70158","DOIUrl":"10.1111/acel.70158","url":null,"abstract":"<p><b>RETRACTION</b>: P. Wang, P.-P. Guan, T. Wang, X. Yu, J.-J. Guo and Z.-Y. Wang, “Aggravation of Alzheimer's Disease due to the COX-2-Mediated Reciprocal Regulation of IL-1β and Aβ Between Glial and Neuron Cells,” <i>Aging Cell</i> 13, no. 4 (2014): 605-615, https://doi.org/10.1111/acel.12209.</p><p>The above article, published online on 13 March 2014 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Monty Montano; the Anatomical Society; and John Wiley &amp; Sons Ltd. The retraction has been agreed upon following an investigation based on concerns raised by a third party. Duplications were uncovered between the NF-κB bands presented in Figure 2C and the β-actin bands in Figure 4K. Further duplication between the β-actin bands in Figures 4E and 5B, 4I and 5A, and between 4J and 5A were also observed. The authors collaborated with our investigation, but due to the time that has elapsed since publication, they were unable to produce any original data. As a result, the editors have lost confidence in the results and conclusions presented in this study. The authors did not confirm agreement with the final wording of the retraction.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 7","pages":""},"PeriodicalIF":7.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70158","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582719","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":"Senescent Microglia Mediate Neuroinflammation-Induced Cognitive Dysfunction by Selective Elimination of Excitatory Synapses in the Hippocampal CA1","authors":"Kai Liu,&nbsp;Di Fan,&nbsp;Hai-peng Wu,&nbsp;Xiao-yi Hu,&nbsp;Qiu-li He,&nbsp;Xin-miao Wu,&nbsp;Cui-na Shi,&nbsp;Jian-jun Yang,&nbsp;Mu-huo Ji","doi":"10.1111/acel.70167","DOIUrl":"10.1111/acel.70167","url":null,"abstract":"<p>Microglia-mediated neuroinflammation has been shown to exert an important effect on the progression of a growing number of neurodegenerative disorders. Prolonged exposure to detrimental stimuli leads to a state of progressive activation and aging-related features in microglia (also termed as senescent microglia). However, the mechanisms by which senescent microglia contribute to neuroinflammation-induced cognitive dysfunction remain to be elucidated. Here, we developed a mouse model of neuroinflammation induced by lipopolysaccharides at 0.5 mg/kg for 7 consecutive days. To evaluate cognitive function, C57BL/6J mice were employed and subjected to a series of behavioral assessments, including the open field, Y-maze, and novel object recognition tests. Employing single-cell RNA sequencing technology, we have delved into the differential expressions of RNA within microglia. Furthermore, to investigate anatomic and physiological alterations of pyramidal neurons, we utilized Golgi staining and whole-cell patch-clamp recordings, respectively. Validation of our results in protein expression was performed using western blotting and immunofluorescence. We specifically identified senescent microglia with a high expression of p16^INK4a and observed that microglia in the hippocampal CA1 region of the model exhibited signatures of elevated phagocytosis and senescence. A senolytic by ABT-737 treatment alleviated the production of senescence-associated secretory phenotypes, the accumulation of senescent microglia, and the microglial hyperphagocytosis of excitatory synapses following LPS exposures. This treatment also restored reduced excitatory synaptic transmission, impaired long-term potentiation, and cognitive function in the model. These results indicate that reducing senescent microglia may potentially serve as a therapeutic approach to prevent neuroinflammation-related cognitive dysfunction.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 9","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582720","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":"Telomere Length, Epigenetic Age Acceleration, and Mortality Risk in US Adult Populations: An Additive Bayesian Network Analysis","authors":"May A. Beydoun,&nbsp;Nicole Noren Hooten,&nbsp;Nigus G. Asefa,&nbsp;Michael F. Georgescu,&nbsp;Minkyo Song,&nbsp;Hind A. Beydoun,&nbsp;Sri Banerjee,&nbsp;Jagdish Khubchandani,&nbsp;Osorio Meirelles,&nbsp;Lenore J. Launer,&nbsp;Michele K. Evans,&nbsp;Alan B. Zonderman","doi":"10.1111/acel.70159","DOIUrl":"10.1111/acel.70159","url":null,"abstract":"<p>Telomere length and DNA methylation (DNAm) clocks serve as markers of biological aging and have been linked to mortality risk. This study applies additive Bayesian networks (ABNs) to examine associations between DNAm clocks, telomere length, and mortality, with a focus on racial and sex differences in aging. Data from three US cohorts—NHANES (<i>n</i> = 2522), HRS (<i>n</i> = 1029), and HANDLS (<i>n</i> = 92–470)—were analyzed using correlation matrices, Cox models, ABNs, and generalized structural equation models (GSEM) with mortality from the National Death Index. Epigenetic clocks, particularly GrimAgeEAA, HannumAgeEAA, and DunedinPoAM (or DunedinPACE), were stronger mortality predictors than telomere length. ABNs highlighted key relationships, consistently linking age and GrimAgeEAA to mortality in NHANES and HRS. GSEM models derived from ABNs indicated an inverse association between female sex and GrimAgeEAA in NHANES (<i>β</i> = −0.500) and HRS (<i>β</i> = −0.563), suggesting slower biological aging in women, although GrimAge clock incorporates sex in its definition. GrimAgeEAA strongly predicted mortality (LnHR, <i>β</i> ± SE of +0.476 ± 0.0393 in NHANES and +0.511 ± 0.0775 in HRS). Non-Hispanic Black adults exhibited accelerated aging via DunedinPoAM, partially mediating their higher mortality risk. Hispanic adults in NHANES had unique associations with PhenoAgeEAA (<i>β</i> = +0.197), a mortality predictor. DNAm clocks, particularly GrimAgeEAA, outperform telomere length in predicting mortality. Second-generation epigenetic aging markers offer insights into demographic disparities in aging and mortality, with ABNs revealing complex interrelations among aging biomarkers, sex, race, and mortality risk.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 9","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574554","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":"SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation","authors":"Marine Barthez,&nbsp;Zehan Song,&nbsp;Yufan Feng,&nbsp;Yifei Wang,&nbsp;Chih-ling Wang,&nbsp;Danica Chen","doi":"10.1111/acel.70162","DOIUrl":"https://doi.org/10.1111/acel.70162","url":null,"abstract":"<p>Aging leads to chronic inflammation that is linked to aging-associated conditions and diseases. Multiple immune pathways become activated during aging, posing a challenge to effectively reduce aging-associated inflammation. SIRT2, an NAD⁺-dependent deacetylase, suppresses several immune pathways that become activated during aging and may represent an attractive target to broadly dampen aging-associated inflammation. Here, we show that SIRT2 deficiency leads to increased inflammation governed by multiple immune pathways and tissue function decline at an old age, while NAD⁺ boosting with 78c suppresses aging-associated inflammation and improves tissue function. These findings highlight SIRT2 as a master regulator of aging-associated inflammation and support NAD⁺ boosting as an effective strategy to counteract aging-associated inflammation and tissue function decline.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 9","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145021977","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":"Coactivator Associated Arginine Methyltransferase 1 Modulates Cartilage Degeneration and Chondrocyte Apoptosis in Osteoarthritis by Regulating ERK1/2 Signaling Pathway","authors":"Jie Yuan,&nbsp;Jingyuan Tian,&nbsp;Ruxing Liu,&nbsp;Xiaoting Qiu,&nbsp;Dongqin He,&nbsp;Guanghui He,&nbsp;Tao Zhang,&nbsp;Pengcui Li,&nbsp;Bin Zhao,&nbsp;Yongfeng Wang","doi":"10.1111/acel.70122","DOIUrl":"10.1111/acel.70122","url":null,"abstract":"<p>This study investigates the role and mechanism of Coactivator Associated Arginine Methyltransferase 1 (CARM1) in osteoarthritis (OA). OA is a prevalent joint disease characterized by cartilage degradation, subchondral bone remodeling, and inflammation. Our research revealed that CARM1 expression is significantly increased in the cartilage tissues of OA patients and OA model mice. Experimental results showed that inhibiting CARM1 reduces cartilage matrix degradation and chondrocyte apoptosis, while overexpression of CARM1 exacerbates these conditions. Mechanistically, CARM1 regulates OA progression through the phosphorylation of the ERK1/2 signaling pathway. Inhibition of CARM1 suppresses ERK1/2 activation, thereby reducing extracellular matrix degradation and chondrocyte apoptosis. These findings suggest that the CARM1-ERK1/2 axis is crucial in modulating cartilage matrix metabolism and chondrocyte apoptosis in OA, highlighting CARM1 as a potential therapeutic target for OA treatment.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70122","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558612","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":"BubR1 Insufficiency Drives Transcriptomic Alterations and Pathology Associated With Cardiac Aging and Heart Failure","authors":"Renju Pun,&nbsp;Aliya L. Haas,&nbsp;Aradhana Thapa,&nbsp;Sylar R. Takafuji,&nbsp;Rexton M. Suzuki,&nbsp;Gabrielle F. Kay,&nbsp;Li Zheng,&nbsp;Michelle Waknitz,&nbsp;Michael H. Kim,&nbsp;Darren J. Baker,&nbsp;Jan M. van Deursen,&nbsp;Paul L. Sorgen,&nbsp;Rebekah L. Gundry,&nbsp;Brian J. North","doi":"10.1111/acel.70160","DOIUrl":"10.1111/acel.70160","url":null,"abstract":"<p>Aging is a prominent risk factor for heart disease, driving pathological cardiac changes such as hypertrophy, fibrosis, and cellular senescence. While BubR1 has been linked to systemic aging in mammalian models, its specific role in regulating cardiac aging remains unclear. Here, we investigated how BubR1 regulates heart aging and its potential contribution to the pathogenesis of cardiac disease, including heart failure. BubR1 insufficiency in mice resulted in marked cardiac hypertrophy, increased fibrosis, and elevated markers of cellular senescence. Transcriptomic profiling revealed widespread disruption in key pathways involved in cardiac function, including ion channel regulation, cytoskeletal organization, and contractile fiber dynamics. Comparative analysis with aged hearts demonstrated shared dysregulated gene networks, linking BubR1 deficiency to age-related cardiac dysfunction. Additionally, BubR1 hypomorphic hearts mirrored transcriptomic changes observed in end-stage heart failure patients, and BubR1 protein levels were found to decline with age in the heart and were also significantly reduced in rodent models of heart failure and in heart failure patients. BubR1 reduction in cardiomyocytes in vitro led to an increased expression of markers of heart failure, hypertrophy, and cytoskeletal remodeling, underscoring an essential and direct role of BubR1 in maintaining cardiomyocyte health. Overall, our data suggest that BubR1 deficiency is a feature of cardiac aging and disease in humans, and that sustaining BubR1 expression may offer a potential therapeutic strategy to mitigate age-associated cardiac decline and improve heart health in the elderly.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 9","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70160","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551495","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}