Aging Cell最新文献

{"title":"Alternative Polyadenylation Contributes to Fibroblast Senescence in Pulmonary Fibrosis","authors":"Jingjing Huang,&nbsp;Maria Jose Gacha-Garay,&nbsp;Yu Wang,&nbsp;Scott D. Collum,&nbsp;Rene A. Girard,&nbsp;Hydia Puente,&nbsp;Seung-Hee Yoo,&nbsp;Rahat Hussain,&nbsp;Jayeshkumar Patel,&nbsp;Manish Patel,&nbsp;Eric J. Wagner,&nbsp;Hari KrishnaYalamanchili,&nbsp;Harry Karmouty-Quintana,&nbsp;Zheng Chen,&nbsp;Tingting Mills","doi":"10.1111/acel.70179","DOIUrl":"10.1111/acel.70179","url":null,"abstract":"<p>Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into pro-inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post-transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA-binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) tail at different sites of 3′ UTR and generates transcript isoforms with different 3′ UTR lengths. We found that NUDT21 was downregulated in aging and fibrotic lungs, particularly at the fibrotic foci of IPF lungs known to have abundant senescent myofibroblasts and collagens. NUDT21 knockdown in normal lung fibroblasts promoted the 3′ UTR shortening of several STAT3 signaling components and enhanced STAT3 phosphorylation and the expression of several SASPs, including interleukins, collagens, and matrix metalloproteinases (MMPs). Moreover, NUDT21 downregulation may be associated with increased fibroblast senescence and abnormal mitochondrial function. Importantly, mice with <i>Nudt21</i> deletion in Col1a1 expressing cells aggravated bleomycin-induced pulmonary fibrosis. Taking together, our study demonstrated an important role of NUDT21-mediated APA in regulating SASP expression and fibroblast senescence that could contribute to the pathogenesis of IPF.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751861","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":"cTAGE5/MEA6 Regulates LBR Localization to Maintain Nuclear Envelope Integrity and Safeguard Against Aging","authors":"Yaqing Wang,&nbsp;Pengyu Sun,&nbsp;Fuqiang Yang,&nbsp;Tiantian Ma,&nbsp;Junwan Fan,&nbsp;Lei Shi,&nbsp;Nan Li,&nbsp;Fei Gao,&nbsp;Kangmin He,&nbsp;Zhiheng Xu","doi":"10.1111/acel.70185","DOIUrl":"10.1111/acel.70185","url":null,"abstract":"<p>cTAGE5/MEA6 plays a pivotal role in COPII complex assembly, ER-to-Golgi trafficking, and secretion. However, whether cTAGE5/MEA6 is involved in other cellular functions remains unclear. Here, we show that conditional <i>cTAGE5</i> knockout results in embryonic lethality during development and premature aging in adult mice. <i>cTAGE5</i> deficiency leads to abnormal nuclear structure and disturbed cell proliferation in MEF cells. Further mechanistic studies reveal that cTAGE5 localizes not only to the ER exit sites but also to other ER structures, where it interacts with the lamin B receptor (LBR). Loss of cTAGE5 disrupts LBR's localization to the inner nuclear membrane, leading to its retention in the ER and instability. This results in abnormal nuclear (envelope) morphology and cellular senescence, likely driven by activation of the P53/P21 senescence pathway. Thus, our study uncovers cTAGE5's role in maintaining nuclear envelope integrity and highlights its function and potential mechanism in preventing cellular senescence and animal aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751862","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":"Proteomic Signatures of Epigenetic Age in African Green Monkey Cerebrospinal Fluid and Plasma","authors":"John D. Elsworth,&nbsp;Albert Neutzner,&nbsp;Julien Roux,&nbsp;Juozas Gordevicius,&nbsp;Milda Milciute,&nbsp;Loveness Dzikiti,&nbsp;Dustin R. Wakeman,&nbsp;Brooke Danielsson,&nbsp;Cavit Agca,&nbsp;Matthew S. Lawrence","doi":"10.1111/acel.70168","DOIUrl":"10.1111/acel.70168","url":null,"abstract":"<p>Strategies to slow the aging process or mitigate its consequences on health rely on the validation of minimally-invasive biomarkers of aging that can be used to track aging and test the effectiveness of antiaging interventions. Study of aging in a nonhuman primate species offers a robust translational approach to achieving these aims, avoiding wide differences in genetics and environmental exposures that confound human aging studies. As epigenetic age appears to predict biological aging, biomarkers linked to epigenetic aging should be especially valuable in identifying individual differences in aging progression and documenting the impact of antiaging strategies. Proteins are the final effectors in most signaling pathways, indicating that alteration in levels of circulating proteins potentially offers an informative and valuable quantitative index of aging. Accordingly, a proteomic analysis was conducted on matching CSF and plasma samples collected from a large group of African green monkeys, with epigenetic ages ranging from young to old as determined by differential methylation of blood DNA. In addition to analyzing the data with linear statistical models, a gradient boosting machine learning technique was employed to identify not only individual CSF and plasma proteins that correlated with aging progression but also groups of proteins that could be used as predictors of global aging and of specialized aspects of aging such as inflammation. Overall, this study identified new CSF and plasma protein targets for understanding aging biology, together with identifying biomarkers to track changes in the rate of biological aging in a translationally relevant nonhuman primate model.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740726","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":"Epigenetic Age Monitoring in Professional Soccer Players for Tracking Recovery and the Effects of Strenuous Exercise","authors":"Robert T. Brooke,&nbsp;Thomas Kocher,&nbsp;Roland Zauner,&nbsp;Juozas Gordevicius,&nbsp;Milda Milčiūtė,&nbsp;Marc Nowakowski,&nbsp;Christian Haser,&nbsp;Thomas Blobel,&nbsp;Johanna Sieland,&nbsp;Daniel Langhoff,&nbsp;Winfried Banzer,&nbsp;Steve Horvath,&nbsp;Florian Pfab","doi":"10.1111/acel.70182","DOIUrl":"10.1111/acel.70182","url":null,"abstract":"<p>Elite sports have become increasingly professionalized and personalized, with soccer players facing a high number of games per season. This trend presents significant challenges in optimizing training for peak performance and requires rigorous monitoring of athletes to prevent overload and reduce injury risks. The emerging field of epigenetic clocks offers promising new pathways for developing useful biomarkers that enhance training management. This study investigates the effects of intense physical activity on epigenetic age markers in professional soccer players across multiple games and during a championship season. We analyzed DNA methylation data from saliva samples collected before and after physical activity. Vigorous physical activity was found to rejuvenate epigenetic clocks, with significant decreases in DNAmGrimAge2 and DNAmFitAge observed immediately after games. Among player subgroups, midfielders exhibited the most substantial epigenetic rejuvenation effect following games. Additionally, the study suggests a potential link between DNA methylation patterns and injury occurrence. Overall, our study suggests that DNA methylation-based biomarkers may have applications in monitoring athlete performance and managing physical stress.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726171","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":"Tissue-Specific Effects of Dietary Protein on Cellular Senescence Are Mediated by Branched-Chain Amino Acids","authors":"Mariah F. Calubag,&nbsp;Ismail Ademi,&nbsp;Isaac D. Grunow,&nbsp;Lucia E. Breuer,&nbsp;Reji Babygirija,&nbsp;Penelope Lialios,&nbsp;Sandra M. Le,&nbsp;Michelle M. Sonsalla,&nbsp;Julia A. Illiano,&nbsp;Bailey A. Knopf,&nbsp;Fan Xiao,&nbsp;Dennis Minton,&nbsp;Adam R. Konopka,&nbsp;David A. Harris,&nbsp;Dudley W. Lamming","doi":"10.1111/acel.70176","DOIUrl":"10.1111/acel.70176","url":null,"abstract":"<p>Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched-chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA-restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age-related diseases, in the liver of mice. Here, we test the hypothesis that the effects of high protein diets on metabolic health and on cellular senescence are mediated by BCAAs. We find that reducing dietary levels of BCAAs protects male mice from the negative metabolic consequences of both normal and high protein diets. Further, we identify tissue-specific effects of BCAAs on cellular senescence, with restriction of all three BCAAs—but not individual BCAAs—protecting from hepatic cellular senescence while potentiating cellular senescence in white adipose tissue. We also find that these effects are sex-specific. We find that the effects of BCAAs on hepatic cellular senescence are cell-autonomous, with lower levels of BCAAs protecting cultured cells from antimycin-A induced senescence. Our results demonstrate a direct effect of a specific dietary component on a hallmark of aging and suggest that cellular senescence may be highly susceptible to dietary interventions.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70176","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726173","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":"Single-Cell Sequencing Reveals That CD4+ T Cells Eliminate Senescent Prostate Epithelium to Delay Progression of Benign Prostatic Hyperplasia","authors":"Zheng Li,&nbsp;Xiaofei Wang,&nbsp;Zhifu Liu,&nbsp;Senmao Li,&nbsp;Zhenan Zhang,&nbsp;Chenchen Huang,&nbsp;Yixiao Liu,&nbsp;Xingxing Tang,&nbsp;Jiaen Zhang,&nbsp;Peimin Zhou,&nbsp;Ying Gan,&nbsp;Yu Fan,&nbsp;Yisen Meng,&nbsp;Kaiwei Yang,&nbsp;Shuai Hu,&nbsp;Qian Zhang,&nbsp;Wei Yu","doi":"10.1111/acel.70180","DOIUrl":"10.1111/acel.70180","url":null,"abstract":"<p>Benign prostatic hyperplasia (BPH) is an age-related condition characterized by progressive prostate enlargement driven in part by the accumulation of senescent epithelial cells and their pro-inflammatory secretome. Using human single-cell RNA sequencing and laser capture microdissection, we identified C-X-C Motif Chemokine Ligand 13 (CXCL13) as a key chemokine secreted by senescent prostate epithelial cells. CXCL13 recruits CD4⁺ T cells via the C-X-C Chemokine Receptor Type 5 (CXCR5) receptor, facilitating immune recognition through human leukocyte antigen–DR isotype (HLA-DR) and promoting senescent cell clearance. Functional assays revealed that CD4⁺ cytotoxic T lymphocytes (CTLs) mediate this clearance, while regulatory T cells (Tregs) suppress it, forming a functional dichotomy. Immunohistochemistry, transwell migration, and co-culture assays confirmed this CXCL13–CXCR5–HLA-DR axis. In a testosterone-induced BPH mouse model, CXCL13 treatment enhanced CD4⁺ T cell infiltration and reduced epithelial senescence, while CD4⁺ T cell depletion reversed these effects. Single-cell transcriptomics in mice further validated increased CXCL13 expression and CD4⁺ T cell engagement. These findings uncover a critical immune surveillance mechanism in BPH and suggest that targeting the CXCL13–CD4⁺ T cell axis may offer a novel therapeutic strategy for age-related prostate enlargement.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726172","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":"Aerobic Exercise Attenuates Autophagy-Lysosomal Flux Deficits via β2-AR-Mediated ESCRT-III Subunit CHMP4B in Mice With Human MAPT P301L","authors":"Shu-Guang Bi,&nbsp;Haitao Yu,&nbsp;Tian-Long Gao,&nbsp;Jia-Jun Wu,&nbsp;Yu-Ming Mao,&nbsp;Juan Gong,&nbsp;Fang-Zhou Wang,&nbsp;Liu Yang,&nbsp;Jia Chen,&nbsp;Zi-Chong Lan,&nbsp;Meng-Ting Shen,&nbsp;Yun-Juan Nie,&nbsp;Gao-Shang Chai","doi":"10.1111/acel.70184","DOIUrl":"10.1111/acel.70184","url":null,"abstract":"<p>Deficits in the autophagy-lysosomal pathway facilitate intracellular microtubule associated protein tau (MAPT) accumulation in Alzheimer disease (AD). Aerobic exercise (AE) has been recommended as a way to delay and treat AD, but the exact effects and mechanisms have not been fully elucidated. Here, we found that AE (8-week treadmill running, 40 min/day, 5 days/week) alleviated autophagy-lysosomal defects and MAPT pathology through the activation of β2-adrenergic receptors (β2-AR) in MAPT P301L mice. Molecular mechanistic investigations revealed that endosomal sorting complex required for transport (ESCRT) III subunit charged multivesicular body protein 4B (CHMP4B), which is essential for autophagosome-lysosome fusion, was significantly decreased in the cerebral cortex of AD patients and the hippocampus of MAPT P301L mice. AE restored the levels of CHMP4B, which reversed autophagy-lysosomal defects and reduced MAPT aggregation. Inhibition of β2-AR by propranolol (30 mg/kg, intragastric administration 1 h before each AE session) restrained AE-attenuated MAPT accumulation by inhibiting autophagy-lysosomal flux in MAPT P301L mice. Our findings suggest that AE can alleviate autophagosome-lysosome fusion deficits by promoting the β2-AR-RXRα-CHMP4B-ESCRT–III pathway, reducing pathological MAPT aggregation, which also reveals a novel theoretical basis for AE attenuating AD progression.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70184","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717095","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":"Pre-Vaccination Immunotypes and Immune Entropy Are Indicators of Multiple Vaccine Responsiveness","authors":"Alper Cevirgel,&nbsp;Marieke van der Heiden,&nbsp;Sudarshan A. Shetty,&nbsp;Markus Viljanen,&nbsp;Martijn Vos,&nbsp;Elske Bijvank,&nbsp;Yannick van Sleen,&nbsp;Celine Imhof,&nbsp;Joeri A. J. Rolwes,&nbsp;Leonard Daniël Samson,&nbsp;Lisa Beckers,&nbsp;Nynke Rots,&nbsp;Josine van Beek,&nbsp;Anne-Marie Buisman,&nbsp;Debbie van Baarle","doi":"10.1111/acel.70151","DOIUrl":"10.1111/acel.70151","url":null,"abstract":"<p>Immune aging is associated with decreased vaccine responses, but biomarkers for vaccine responsiveness remain unidentified. We analyzed immunotypes describing pre-vaccination immune cell profiles and their associations with triple vaccine responsiveness to influenza, pneumococcal, and SARS-CoV-2 vaccines in adults aged 25–78 years. Additionally, we developed an innovative measure, immune entropy, to quantify cumulative perturbations in the immune cell subset network. Specific immunotypes were associated with either weak or robust triple vaccine responsiveness. In addition, immune entropy was inversely related to vaccine responsiveness regardless of age. In a validation cohort of older adults, higher immune entropy was also associated with a lower antibody response to the BNT162b2 vaccine. A separate cohort of kidney transplant recipients, typically exhibiting diminished vaccine responses, demonstrated significantly increased immune entropy compared to healthy counterparts. Our findings suggest immunotypes and immune entropy as potential indicators to identify individuals at risk for suboptimal vaccine responses, potentially guiding personalized vaccination strategies.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 9","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70151","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697177","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":"Rapamycin Does Not Compromise Exercise-Induced Muscular Adaptations in Female Mice","authors":"Christian J. Elliehausen,&nbsp;Szczepan S. Olszewski,&nbsp;Dennis M. Minton,&nbsp;Carolyn G. Shult,&nbsp;Aditya R. Ailiani,&nbsp;Michaela E. Trautman,&nbsp;Reji Babygirija,&nbsp;Dudley W. Lamming,&nbsp;Troy A. Hornberger,&nbsp;Adam R. Konopka","doi":"10.1111/acel.70183","DOIUrl":"10.1111/acel.70183","url":null,"abstract":"<p>An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with the goal of extending healthspan. However, frequent rapamycin dosing disrupts metabolic health during sedentary conditions and abates the anabolic response to exercise. Intermittent once-weekly rapamycin dosing minimizes many negative metabolic side effects of frequent rapamycin in sedentary mice. However, it remains unknown how different rapamycin dosing schedules impact metabolic, physical, and skeletal muscle adaptations to voluntary exercise training. Therefore, we tested the hypothesis that intermittent rapamycin (2 mg/kg; 1×/week) would avoid detrimental effects on adaptations to 8 weeks of progressive weighted wheel running (PoWeR) in adult female mice (5-month-old) by evading the sustained inhibitory effects on mTOR signaling by more frequent dosing schedules (2 mg/kg; 3×/week). PoWeR improved maximal exercise capacity, absolute grip strength, and myofiber hypertrophy with no differences between vehicle or rapamycin-treated mice despite greater voluntary running volume with intermittent rapamycin treatment. Conversely, frequent and intermittent rapamycin-treated mice had impaired glucose tolerance and insulin sensitivity compared to vehicle-treated mice after PoWeR; however, intermittent rapamycin reduced the impact on glucose intolerance versus frequent rapamycin. Collectively, these data in adult female mice suggest that (1) rapamycin is largely compatible with the physical and skeletal muscle benefits of PoWeR and (2) the detrimental effects of rapamycin on glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70183","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697178","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":"Skeletal Maturity and Age-Related Changes in Immune Cells and Circulatory Factors Impair Large-Scale Bone Regeneration","authors":"Luciana Yamamoto de Almeida,&nbsp;Catharine Dietrich,&nbsp;Ashleigh S. Hanner,&nbsp;Katelyn M. McTighe,&nbsp;Daniel Martin,&nbsp;NIDCD/NIDCR Genomics and Computational Biology Core,&nbsp;Todd Fairbanks,&nbsp;Thomas M. Link,&nbsp;John M. Le,&nbsp;Natasha Curry,&nbsp;Priyam Jani,&nbsp;Xin Gao,&nbsp;Wenli Yu,&nbsp;Francesca V. Mariani,&nbsp;Olivier Duverger,&nbsp;Janice S. Lee","doi":"10.1111/acel.70177","DOIUrl":"10.1111/acel.70177","url":null,"abstract":"<p>Large-scale bone defects require complex surgical procedures to repair, but full restoration of the bone is not guaranteed due to the significant tissue loss involved. In contrast, fractures can frequently be treated with conservative techniques. Particularly, ribs have a remarkable ability to spontaneously regenerate large-scale bone defects. However, we show here that skeletal maturity and age are associated with a decrease in the regenerative potential of human ribs. To investigate skeletal maturity and age-related cellular and transcriptional changes during large-scale bone regeneration, we used a mouse model that mimics the regenerative clinical features of human ribs. Unlike immature mice, mature mice lose the ability to regenerate after rib resection, and instead of bone, the resected rib space is repaired with abundant fibronectin cells. In addition, bone repair in mature mice presents reduced immune cell infiltration, which coincides with decreased levels of circulatory pro-inflammatory factors. To address the role of cell–cell communication and test whether skeletal maturity and age-related changes in immune cells and circulatory factors influence bone regeneration, we used immunodeficient mouse strains and performed heterochronic parabiosis. In immature mice, defective immune cell function altered callus composition rather than inhibiting bone regeneration. Remarkably, under parabiosis, a systemic pro-regenerative response is triggered exclusively in resected immature mice and is capable of partially rescuing bone regeneration in mature mice otherwise unable to regenerate spontaneously. Collectively, these findings suggest that therapeutic strategies focused on identifying pro-regenerative immune factors are promising for supporting the regeneration of large bone defects.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673412","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}