Aging Cell最新文献

{"title":"Effects of the VIVIFRAIL Exercise Protocol on Circulatory and Intracellular Peripheral Mediators Bridging Mitochondrial Dynamics and Inflammation in Robust and Frail Older People.","authors":"Fiona Limanaqi, Evelyn Ferri, Pasquale Ogno, Franca Rosa Guerini, Gabriela Alexandra Mihali, Tiziano Lucchi, Mario Clerici, Chiara Fenoglio, Laura D'Andrea, Elena Marcello, Mara Biasin, Beatrice Arosio","doi":"10.1111/acel.70029","DOIUrl":"https://doi.org/10.1111/acel.70029","url":null,"abstract":"<p><p>Physical exercise has been associated with healthier aging trajectories, potentially preventing or mitigating age-related declines. This occurs through a complex, yet poorly characterized network of multi-organ interactions involving mitochondrial, inflammatory, and cell death/survival pathways. Here, we comprehensively evaluated the 12-week VIVIFRAIL multicomponent exercise protocol in physically frail (n = 16, mean age 81.4 ± 5.6) and robust (n = 50, mean-age 73.6 ± 4.7) old individuals. Before (T0) and after (T1) the protocol, functional outcomes were assessed alongside a detailed exploratory analysis of mitochondrial, inflammatory, apoptotic, and neuro-muscular mediators concerning their plasmatic/serum concentrations, and/or mRNA expression from peripheral blood mononuclear cells (PBMCs). Besides significant functional improvements across both groups, our findings highlighted unique and overlapping modulations of key biological pathways. Both groups showed refined mitochondrial integrity/turnover (upregulated mt-ND1, downregulated TFAM, and ULK1), anti-inflammatory responses (upregulated IL10, and TGF-B, and downregulated IL6/IL10 mRNA ratio), as well as reduced cellular damage/apoptosis (reduced plasmatic ccf-nDNA, downregulated BAX, and upregulated BCL-2/BAX ratio). Plasmatic ccf-mtDNA was significantly reduced in robust subjects, while plasmatic IL6 and IL6/IL10 ratio were reduced in frail subjects uniquely. Spearman correlations between physical improvements and biological pathway variations also suggested different adaptation mechanisms influenced not only by chronological age but also by frailty status. In conclusion, this study confirms the benefits of physical activity in the older population and provides novel insights into specific biological mediators of the mitochondria-inflammation axis as key players in such effects. Moreover, our findings establish PBMCs as a valuable tool for monitoring the biological trajectories of aging and health-promoting lifestyle interventions.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70029"},"PeriodicalIF":8.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rejuvenation of Senescent Cells, In Vitro and In Vivo, by Low-Frequency Ultrasound.","authors":"Sanjay K Kureel, Rosario Maroto, Maisha Aniqua, Simon Powell, Ekta Singh, Felix Margadant, Brandon Blair, Blake B Rasmussen, Michael P Sheetz","doi":"10.1111/acel.70008","DOIUrl":"https://doi.org/10.1111/acel.70008","url":null,"abstract":"<p><p>The presence of senescent cells causes age-related pathologies since their removal by genetic or pharmacological means, as well as possibly by exercise, improves outcomes in animal models. An alternative to depleting such cells would be to rejuvenate them to promote their return to a replicative state. Here we report that treatment of non-growing senescent cells with low-frequency ultrasound (LFU) rejuvenates the cells for growth. Notably, there are 15 characteristics of senescent cells that are reversed by LFU, including senescence-associated secretory phenotype (SASP) plus decreased cell and organelle motility. There is also inhibition of β-galactosidase, p21, and p16 expression, telomere length is increased, while nuclear 5mC, H3K9me3, γH2AX, nuclear p53, ROS, and mitoSox levels are all restored to normal levels. Mechanistically, LFU causes Ca²⁺ entry and increased actin dynamics that precede dramatic increases in autophagy and an inhibition of mTORC1 signaling plus movement of Sirtuin1 from the nucleus to the cytoplasm. Repeated LFU treatments enable the expansion of primary cells and stem cells beyond normal replicative limits without altering phenotype. The rejuvenation process is enhanced by co-treatment with cytochalasin D, rapamycin, or Rho kinase inhibition but is inhibited by blocking Sirtuin1 or Piezo1 activity. Optimized LFU treatment parameters increased mouse lifespan and healthspan. These results indicate that mechanically induced pressure waves alone can reverse senescence and aging effects at the cellular and organismal level, providing a non-pharmacological way to treat the effects of aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70008"},"PeriodicalIF":8.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetes Advances Cardiomyocyte Senescence Through Interfering Rnd3 Expression and Function.","authors":"Linxu Wu, Xinglin Zhu, Shanshan Pan, Yan Chen, Cai Luo, Yangyang Zhao, Jingci Xing, Kaijia Shi, Shuya Zhang, Jiaqi Li, Jinxuan Chai, Xuebin Ling, Jianmin Qiu, Yan Wang, Zhihua Shen, Wei Jie, Junli Guo","doi":"10.1111/acel.70031","DOIUrl":"https://doi.org/10.1111/acel.70031","url":null,"abstract":"<p><p>Rnd3 is a small Rho-GTPase that has been implicated in various cardiovascular diseases. Yet, its role in diabetes-induced cardiomyocyte senescence remains unknown. Here we tested the role of Rnd3 in cardiomyocyte senescence and diabetic cardiomyopathy (DCM). The expression of Rnd3 was found to be reduced in peripheral blood mononuclear cells from diabetic patients and correlated negatively with age but positively with cardiac function. In 96-week-old Sprague Dawley (SD) rats, cardiac function was impaired, accompanied by an increased number of SA-β-gal-positive cells and elevated levels of the senescence-associated secretory phenotype (SASP) related factors, compared to those of 12-week-old rats. Diabetes and high glucose (HG, 35 mmol/L D-glucose) suppressed Rnd3 expression in cardiomyocytes and induced cardiomyocyte senescence. The deficiency of Rnd3 exacerbated cardiomyocyte senescence in vitro and in vivo. MicroRNA sequencing in AC16 cells identified a conserved miR-103a-3p (present in humans and rats) as a key HG-upregulated microRNA that bound to the Rnd3 3'-UTR. In cultured cardiomyocytes, miR-103a-3p inhibitors antagonized HG-induced cardiomyocyte senescence dependent on Rnd3 expression. Treatment with AAV9 vectors carrying miR-103a-3p sponges and Rnd3-overexpressing plasmids alleviated cardiomyocyte senescence and restored cardiac function in diabetic SD rats. HG stimulation increased STAT3 (Tyr705) phosphorylation and promoted its nuclear translocation in H9C2 cells, an effect exacerbated by Rnd3 knockout. Mechanistically, Rnd3 interacted with p-STAT3 in the cytoplasm, facilitating proteasome-mediated ubiquitination and p-STAT3 degradation. The STAT3 inhibitor S3I-201 blocked HG-induced STAT3 activation and mitigated cardiomyocyte senescence. These findings suggest that diabetes induces cardiomyocyte senescence via the miR-103a-3p/Rnd3/STAT3 signaling pathway, highlighting a potential therapeutic target for DCM.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70031"},"PeriodicalIF":8.0,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming Growth Factor-β-Activated Protein 1 (TAK1) Regulates Necroptosis in Age-Related Hearing Loss.","authors":"Hanjing Wang, Yayun Lv, He Zhao, Zhihong Hao, Xiaoyu Zhai, Yan Wang, Jingjing Qiu, Liang Chen, Jiamin Zhou, Limei Cui, Yan Sun","doi":"10.1111/acel.70013","DOIUrl":"https://doi.org/10.1111/acel.70013","url":null,"abstract":"<p><p>Inflammation plays an important role in age-related hearing loss (ARHL). Transforming growth factor-β-activated protein 1 (TAK1), a key factor upstream of inflammatory pathways, mediates various cell death pathways, potentially influencing the survival and death of cochlear hair cells. The DBA/2 J mouse model and the HEI-OC1 cell line were used to investigate the mechanism of TAK1-mediated inflammation in ARHL. Hematoxylin and eosin staining revealed significant histological damage in the cochlea of 16-week-old mice, along with an increase in auditory-evoked brainstem response thresholds. Concurrently, TAK1 mRNA levels decreased sharply, and necroptosis significantly increased in 16-week-old mice, indicating a correlation between TAK1 expression, necroptosis, and hearing loss. We subsequently constructed TAK1 knockdown and overexpression HEI-OC1 cells for further investigation. TAK1 knockdown in HEI-OC1 cells significantly activated the necroptotic pathway, characterized by an increase in necroptosis, along with up-regulation of RIPK3 and MLKL, and down-regulation of NF-κB and Caspase 8. However, TAK1 overexpression successfully prevented necroptosis in HEI-OC1 cells, leading to decreases in NF-κB, Caspase 8, RIPK3, and MLKL. We further treated TAK1 knockdown cells with necroptosis inhibitors and found that they could reverse the damage caused by TAK1 knockdown in HEI-OC1 cells. This preliminary study shows that TAK1-mediated necroptotic pathways play an important role in the pathogenesis of ARHL.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70013"},"PeriodicalIF":8.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of Advancing Age and Intraocular Pressure Injury on Retinal Ganglion Cell Function and Synaptic Connectivity.","authors":"Vicki Chrysostomou, Sevannah Ellis, Lewis E Fry, Robert J Hatch, Eamonn T Fahy, Katharina C Bell, Ian A Trounce, Peter van Wijngaarden, Steve Petrou, Jonathan G Crowston","doi":"10.1111/acel.70005","DOIUrl":"https://doi.org/10.1111/acel.70005","url":null,"abstract":"<p><p>Age and elevated intraocular pressure (IOP) are the two major risk factors for developing glaucoma, a leading cause of blindness worldwide that is characterized by the loss of retinal ganglion cells (RGCs). Although vision loss is irreversible over the long term, accumulating evidence points to short-term improvement of vision in glaucoma patients in response to certain interventions, suggesting that RGCs have the capacity to recover function. In the present study, we sought to investigate the mechanisms underlying loss and recovery of RGC function in response to aging and IOP injury, with a focus on synaptic connectivity. Using electroretinography, we found that advancing age was associated with a substantial reduction in function across all retinal layers in the absence of significant cell loss. A superimposed injury induced by IOP elevation led to the selective loss of RGC function in young and middle-aged mice that was associated with a decrease in paired excitatory synapses. RGC functional recovery after injury was significantly delayed in middle-aged mice and was mediated through different cellular mechanisms than in young mice. Whereas young mice regained excitatory synaptic inputs from bipolar cells, functional recovery in older mice was instead mediated through an increase in intrinsic RGC excitability, associated with modulation of the action potential threshold and axon initial segment length. Our findings provide new insights into the impact of advancing age on RGC resilience to IOP injury. Boosting the capacity for RGC recovery by reversing the effect of advancing age offers a new therapeutic approach for glaucoma management.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70005"},"PeriodicalIF":8.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circular RNA Telomerase Reverses Endothelial Senescence in Progeria.","authors":"Weifeng Qin, Kathrina D Castillo, Hongye Li, Thi Kim Cuc Nguyen, Daniel L Kiss, John P Cooke, Anahita Mojiri","doi":"10.1111/acel.70021","DOIUrl":"https://doi.org/10.1111/acel.70021","url":null,"abstract":"<p><p>Telomeres shorten with each cell division, acting as a chronometer of cell age. The enzyme telomerase, primarily active in stem cells, reverses telomere erosion. We have previously observed that transient transfection with human TERT mRNA extends telomeres and mitigates hallmarks of senescence in replicatively aged human cells or those affected by Hutchinson-Gilford progeroid syndrome (HGPS). However, due to its short half-life, mRNA requires frequent administration. In this study, we hypothesized that TERT circular (circ) RNA would extend the duration of telomerase expression and be more effective at reversing hallmarks of senescence in endothelial cells derived from HGPS patients. We observe that a single transfection of TERT circRNA is more effective than mRNA in the extension of telomere length, as determined by quantitative fluorescence in situ hybridization. Furthermore, TERT circRNA reduced the number of β-gal positive cells by three-fold and normalized nuclear morphology in HGPS endothelial cells (HGPS-ECs). Moreover, TERT circRNA substantially reduced senescent markers, inflammatory markers, and DNA damage markers, including Progerin, p16, p21, IL-1B, IL-6, IL-8, MCP1, and γH2AX. Additionally, it restored NO production, enhanced cell proliferation, promoted angiogenesis, improved LDL uptake, reduced mitochondrial ROS, and normalized mitochondrial membrane potential more effectively. Our data suggest that TERT circRNA is superior to linear TERT mRNA in reversing processes involved in senescence.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70021"},"PeriodicalIF":8.0,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-Dependent Clonal Expansion of Non-Sperm-Forming Spermatogonial Stem Cells in Mouse Testes.","authors":"Terumichi Kawahara, Shinnosuke Suzuki, Toshinori Nakagawa, Yuki Kamo, Miki Kanouchi, Miyako Fujita, Maki Hattori, Atsuko Suzuki, Kentaro Tanemura, Shosei Yoshida, Kenshiro Hara","doi":"10.1111/acel.70019","DOIUrl":"https://doi.org/10.1111/acel.70019","url":null,"abstract":"<p><p>In male mammals, spermatogonial stem cells (SSCs) are essential for sustaining lifelong spermatogenesis within the testicular open niche, a unique environment that allows SSC migration over an extended niche area. As SSCs undergo continuous mitotic division, mutations accumulate and are transmitted to the descendant SSC clones. Therefore, SSC clonal fate behaviors, in terms of their efficiencies in completing spermatogenesis and undergoing expansion within the niche, influence sperm genomic diversity. We aimed to elucidate the effects of physiological aging on SSC clonal fate behavior within the testicular open niche. We used single-cell RNA sequencing, lineage tracing, and intravital live imaging to investigate SSC behavior in aged mouse testes, where spermatogenesis, although reduced, persists. We found that undifferentiated spermatogonia maintained gene expression heterogeneity during aging. Among these, GFRα1⁺ cells, which exhibited state heterogeneity, showed accelerated proliferation and persistent motility, continuing to function as SSCs in older mice. In contrast, a subset of SSCs characterized by low Egr4 and Cops5 expression did not contribute to spermatid formation. These non-sperm-forming SSC clones increased in proportion among the total SSC clones and expanded spatially within the testicular open niche in old mice, a phenomenon not observed in young mice. The expansion of non-sperm-forming SSC clones in aged testes suggests that they occupy a niche space, limiting the availability of functional SSCs and potentially reducing sperm production and genetic diversity. These findings highlight age-specific clonal characteristics as hallmarks of stem cell aging within the testicular open niche and provide novel insights into the mechanisms governing reproductive aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70019"},"PeriodicalIF":8.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-Scale Clustered Transcriptional Silencing Associated With Cellular Senescence.","authors":"Aditi U Gurkar, Satoshi Okawa, Christelle Guillermier, Kritika Chaddha, Matthew L Steinhauser","doi":"10.1111/acel.70015","DOIUrl":"https://doi.org/10.1111/acel.70015","url":null,"abstract":"<p><p>Senescence is a cell fate associated with age-related pathologies; however, senescence markers are not well-defined. Using single cell multi-isotope imaging mass spectrometry (MIMS), we identified hypercondensed, transcriptionally silent DNA globules in a senescence model induced by dysfunctional telomeres. This architectural phenomenon was associated with geographically clustered transcriptional repression across somatic chromosomes with over-representation of cell cycle genes. Senescence-stimuli was associated with a higher frequency of cells that exhibited geographically concentrated transcriptional repression relative to control cells. This phenomenon was also observed in multiple other senescence models, including replicative senescence and irradiation. We further identified an enrichment of common pathways in all models of senescence, suggesting a common cellular response to this silencing phenomenon. Such large-scale clustered silencing of chromosomal segments rather than individual genes may explain senescence heterogeneity and a putative trajectory toward deep, irreversible senescence.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70015"},"PeriodicalIF":8.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activated mTOR Signaling in the RPE Drives EMT, Autophagy, and Metabolic Disruption, Resulting in AMD-Like Pathology in Mice.","authors":"Olivia Chowdhury, Sridhar Bammidi, Pooja Gautam, Vishnu Suresh Babu, Haitao Liu, Peng Shang, Ying Xin, Emma Mahally, Mihir Nemani, Victoria Koontz, Kira Lathrop, Katarzyna M Kedziora, Jonathan Franks, Ming Sun, Joshua W Smith, Lauren R DeVine, Robert N Cole, Nadezda Stepicheva, Anastasia Strizhakova, Sreya Chattopadhyay, Stacey Hose, Jacob Samuel Zigler, José-Alain Sahel, Jiang Qian, Prasun Guha, James T Handa, Sayan Ghosh, Debasish Sinha","doi":"10.1111/acel.70018","DOIUrl":"https://doi.org/10.1111/acel.70018","url":null,"abstract":"<p><p>The mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are crucial for various physiological functions. Although the role of mTORC1 in retinal pigmented epithelium (RPE) homeostasis and age-related macular degeneration (AMD) pathogenesis is established, the function of mTORC2 remains unclear. We investigated both complexes in RPE health and disease. Therefore, in this study, we have attempted to demonstrate that the specific overexpression of mammalian lethal with Sec13 protein 8 (mLST8) in the mouse RPE activates both mTORC1 and mTORC2, inducing epithelial-mesenchymal transition (EMT)-like changes and subretinal/RPE deposits resembling early AMD-like pathogenesis. Aging in these mice leads to RPE degeneration, causing retinal damage, impaired debris clearance, and metabolic and mitochondrial dysfunction. Inhibition of mTOR with TORIN1 in vitro or βA3/A1-crystallin in vivo normalized mTORC1/2 activity and restored function, revealing a novel role for the mTOR complexes in regulating RPE function, impacting retinal health and disease.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70018"},"PeriodicalIF":8.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Toll-Like Receptor 5 on Liver Function in Age-Related Metabolic Disorders.","authors":"Dong-Hyun Kim, Hye Sun Go, Eun Jae Jeon, Thi Quynh Trang Nguyen, Da Yeon Kim, Hansung Park, Hyo-Ji Eom, Sung Young Kim, Sang Chul Park, Kyung A Cho","doi":"10.1111/acel.70009","DOIUrl":"https://doi.org/10.1111/acel.70009","url":null,"abstract":"<p><p>Toll-like receptor 5 (TLR5) plays a critical role beyond its traditional function in innate immunity, significantly impacting metabolic regulation and liver health. Previously, we reported that TLR5 activation extends the healthspan and lifespan of aging mice. This study demonstrates that TLR5 deficiency leads to pronounced metabolic abnormalities with age, primarily affecting liver metabolic functions rather than intestinal inflammation. Comprehensive RNA sequencing analysis revealed that TLR5 deficiency induces gene expression changes in liver tissue similar to those caused by the methionine-choline deficient (MCD) diet, particularly affecting lipid metabolism and circadian rhythm-related genes. TLR5 knockout (TLR5 KO) mice displayed an increased propensity for liver fibrosis and lipid accumulation under the MCD diet, exacerbating liver pathology. Both hepatocytes and hepatic stellate cells in TLR5 KO mice were functionally impacted, leading to metabolic dysfunction and fibrosis. These findings suggest that TLR5 could be a significant target for addressing metabolic diseases that arise and worsen with aging. Furthermore, understanding the mechanisms by which TLR5 activation extends healthspan could provide valuable insights into therapeutic strategies for enhancing longevity and managing age-related metabolic disorders.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70009"},"PeriodicalIF":8.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}