Aging Cell最新文献

{"title":"Epigenetic Age Monitoring in Professional Soccer Players for Tracking Recovery and the Effects of Strenuous Exercise.","authors":"Robert T Brooke, Thomas Kocher, Roland Zauner, Juozas Gordevicius, Milda Milčiūtė, Marc Nowakowski, Christian Haser, Thomas Blobel, Johanna Sieland, Daniel Langhoff, Winfried Banzer, Steve Horvath, Florian Pfab","doi":"10.1111/acel.70182","DOIUrl":"https://doi.org/10.1111/acel.70182","url":null,"abstract":"<p><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":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70182"},"PeriodicalIF":7.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Ismail Ademi, Isaac D Grunow, Lucia E Breuer, Reji Babygirija, Penelope Lialios, Sandra M Le, Michelle M Sonsalla, Julia A Illiano, Bailey A Knopf, Fan Xiao, Dennis Minton, Adam R Konopka, David A Harris, Dudley W Lamming","doi":"10.1111/acel.70176","DOIUrl":"https://doi.org/10.1111/acel.70176","url":null,"abstract":"<p><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":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70176"},"PeriodicalIF":7.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Xiaofei Wang, Zhifu Liu, Senmao Li, Zhenan Zhang, Chenchen Huang, Yixiao Liu, Xingxing Tang, Jiaen Zhang, Peimin Zhou, Ying Gan, Yu Fan, Yisen Meng, Kaiwei Yang, Shuai Hu, Qian Zhang, Wei Yu","doi":"10.1111/acel.70180","DOIUrl":"https://doi.org/10.1111/acel.70180","url":null,"abstract":"<p><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":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70180"},"PeriodicalIF":7.1,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Haitao Yu, Tian-Long Gao, Jia-Jun Wu, Yu-Ming Mao, Juan Gong, Fang-Zhou Wang, Liu Yang, Jia Chen, Zi-Chong Lan, Meng-Ting Shen, Yun-Juan Nie, Gao-Shang Chai","doi":"10.1111/acel.70184","DOIUrl":"https://doi.org/10.1111/acel.70184","url":null,"abstract":"<p><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":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70184"},"PeriodicalIF":8.0,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Marieke van der Heiden, Sudarshan A Shetty, Markus Viljanen, Martijn Vos, Elske Bijvank, Yannick van Sleen, Celine Imhof, Joeri A J Rolwes, Leonard Daniël Samson, Lisa Beckers, Nynke Rots, Josine van Beek, Anne-Marie Buisman, Debbie van Baarle","doi":"10.1111/acel.70151","DOIUrl":"https://doi.org/10.1111/acel.70151","url":null,"abstract":"<p><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":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70151"},"PeriodicalIF":8.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Szczepan S Olszewski, Dennis M Minton, Carolyn G Shult, Aditya R Ailiani, Michaela E Trautman, Reji Babygirija, Dudley W Lamming, Troy A Hornberger, Adam R Konopka","doi":"10.1111/acel.70183","DOIUrl":"10.1111/acel.70183","url":null,"abstract":"<p><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":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70183"},"PeriodicalIF":8.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Catharine Dietrich, Ashleigh S Hanner, Katelyn M McTighe, Daniel Martin, Todd Fairbanks, Thomas M Link, John M Le, Natasha Curry, Priyam Jani, Xin Gao, Wenli Yu, Francesca V Mariani, Olivier Duverger, Janice S Lee","doi":"10.1111/acel.70177","DOIUrl":"https://doi.org/10.1111/acel.70177","url":null,"abstract":"<p><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":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70177"},"PeriodicalIF":8.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smoking Promotes AT2 Cell Senescence and Exacerbates Pulmonary Fibrosis by Downregulating POT1 via Integratively Inducing CpG Methylation and MECP2-Mediated FOXP2 Transcriptional Binding Inhibition.","authors":"Mengkun Shi, Wei Wang, Posum Wan, Jialun Shi, Huixia Cui, Zhonghan Sun, Xiaofeng Chen, Jingyu Chen, Jiucun Wang, Xiangguang Shi","doi":"10.1111/acel.70174","DOIUrl":"https://doi.org/10.1111/acel.70174","url":null,"abstract":"<p><p>Smoking is one of the most recognized risk factors for pulmonary fibrosis (PF). However, the underlying mechanism is not well understood. This study reveals smoking increases the risk of developing idiopathic PF (IPF) and that smoked IPF patients exhibit higher levels of senescence markers than non-smoker IPF patients. Moreover, smoking enhances bleomycin (Bleo)-induced PF, along with obvious senescence of type II alveolar (AT2) cells. RNA-seq assay identifies cigarette downregulates protection of telomeres 1 (POT1), which is then validated to decrease in smoked PF patients and mice via upregulating the methyltransferase MECP2. Mechanistically, MECP2 binds to the DNA methyltransferases (DNMTs)-induced methylated CpG island in the POT1 promoter, and smoking inhibits the transcriptional activity of the CpG island. The transcription factor FOXP2 could bind to this CpG island to promote POT1 transcription. However, this process is inhibited by forming a MECP2-FOXP2 complex, which blunts the FOXP2-POT1 DNA binding. siRNA-mediated POT1 knockdown promoted AT2 cell senescence in a p-ATM and p-ATR-dependent manner and secreted inflammatory and profibrotic factors, further promoting fibrotic response in fibroblasts. In vivo, delivery of the adeno-associated virus 9-POT1 (AAV9-POT1) vector inhibits cigarette-induced cell senescence and effectively alleviates PF in mice. These findings demonstrate that POT1 is an essential protector in PF by protecting against AT2 cell senescence.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70174"},"PeriodicalIF":8.0,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673413","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":"Beyond the Pseudogene: p17/PERMIT as a Mitochondrial Trafficking Protein Linking Aging and Neurodegeneration.","authors":"Onder Albayram, Natalia Oleinik, Besim Ogretmen","doi":"10.1111/acel.70175","DOIUrl":"https://doi.org/10.1111/acel.70175","url":null,"abstract":"<p><p>The misclassification of functional genomic loci as pseudogenes has long obscured critical regulators of cellular homeostasis, particularly in aging-related pathways. One such locus, originally annotated as RPL29P31, encodes a 17-kDa protein now redefined as PERMIT (Protein that Mediates ER-Mitochondria Trafficking). Through rigorous experimental validation-including antibody development, gene editing, lipidomics, and translational models-p17/PERMIT has emerged as a previously unrecognized mitochondrial trafficking chaperone. Under aging or injury-induced stress, p17 mediates the ER-to-mitochondria translocation of Ceramide Synthase 1 (CerS1), facilitating localized C18-ceramide synthesis and autophagosome recruitment to initiate mitophagy. Loss of p17 impairs mitochondrial quality control, accelerating neurodegeneration, and sensorimotor decline in both injury and aging models. This Perspective highlights p17 as a paradigm-shifting discovery at the intersection of lipid signaling, mitochondrial biology, and genome reannotation, and calls for a broader reassessment of the \"noncoding\" genome in aging research. We summarize a rigorous multi-platform validation pipeline-including gene editing, antibody generation, lipidomics, proteomics, and functional rescue assays-that reclassified p17 as a bona fide mitochondrial trafficking protein. Positioned at the intersection of lipid metabolism, organelle dynamics, and genome reannotation, p17 exemplifies a growing class of overlooked proteins emerging from loci historically labeled as pseudogenes, urging a systematic reevaluation of the \"noncoding\" genome in aging research.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70175"},"PeriodicalIF":8.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648067","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 Histone Deacetylase 3 Regulation by βA3/A1-Crystallin and Inositol Hexaphosphate in Retinal Pigmented Epithelial Cells Reveals a Novel Pathway in Age-Related Macular Degeneration.","authors":"Sujan Chatterjee, Sayan Ghosh, Zachary Sin, Vishnu Suresh Babu, Loretta Viera Preval, Emily Davis, Nguyen Tran, Sridhar Bammidi, Pooja Gautam, Stacey Hose, Yuri Sergeev, Miguel Flores-Bellver, Kevin Ritter, Henning J Jessen, Issam Al Diri, Debasish Sinha, Prasun Guha","doi":"10.1111/acel.70163","DOIUrl":"10.1111/acel.70163","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD), a leading cause of vision loss affecting retinal pigment epithelial (RPE) cells, remains largely unexplained by current genome-wide association studies (GWAS) risk variants. Our research on Cryba1, encoding βA3/A1-crystallin protein, reveals its crucial role in RPE cell function via a novel epigenetic mechanism, also evident in human atrophic AMD samples. Loss of Cryba1 in mouse RPE cells triggers epigenetic changes by reducing histone deacetylase 3 (HDAC3) activity through two mechanisms. First, Cryba1 depletion reduces inositol polyphosphate multikinase (IPMK) expression, which potentially reduces inositol hexakisphosphate (InsP6) generation since IPMK's kinase activity is essential for producing InsP4 and InsP5 as precursors to InsP6. Since InsP4, InsP5, or InsP6 is crucial for HDAC3's interaction with the corepressor's DAD domains, reduced IPMK expression in Cryba1-depleted cells likely diminishes the HDAC3-DAD interaction, leading to a reduction in HDAC3's activity. Second, reduced βA3/A1 protein in Cryba1-deficient cells impairs HDAC3's interaction with casein kinase 2 (CK2), resulting in decreased HDAC3 phosphorylation. Collectively, this increases H3K27 acetylation at the RET promoter region, likely enhancing the transcription of RET, a receptor tyrosine kinase critical for cell survival. Although RET is transcriptionally increased, Cryba1 loss disrupts its protein maturation, causing immature RET protein accumulation. This triggers age-dependent endoplasmic reticulum (ER) stress, potentially contributing to the pathogenesis of AMD. Interestingly, although Cryba1 is not identified as an AMD-linked variant in current GWAS, its loss may be linked to AMD mechanisms. These findings underscore the potential of gene-agnostic and epigenetic therapeutic strategies for treating AMD.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70163"},"PeriodicalIF":8.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635785","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}