Aging Cell最新文献

{"title":"Aging-Associated Liver Sinusoidal Endothelial Cells Dysfunction Aggravates the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease.","authors":"Qingqing Dai, Quratul Ain, Navodita Seth, Hongchuan Zhao, Michael Rooney, Alexander Zipprich","doi":"10.1111/acel.14502","DOIUrl":"https://doi.org/10.1111/acel.14502","url":null,"abstract":"<p><p>Aging increases the susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD). Liver sinusoidal endothelial cells (LSECs) help in maintaining hepatic homeostasis, but the contribution of age-associated LSECs dysfunction to MASLD is not clear. The aim of this study was to investigate the effect of aging-associated LSECs dysfunction on MASLD. Free fatty acid-treated AML12 cells were co-cultured with young and etoposide-induced senescent TSEC cells to evaluate the senescence-associated endothelial effects on the lipid accumulation in hepatocytes. In addition, young and aged rats were subjected to methionine-choline-deficient diet-induced metabolic dysfunction-associated steatohepatitis (MASH). Hepatic hemodynamics and endothelial dysfunction were evaluated by in situ liver perfusion. Liver tissue samples from young and aged healthy controls and MASH patients were also analyzed. Steatotic AML12 cells co-cultured with young TSEC cells showed less lipid accumulation, and such effect was abolished by eNOS inhibitor or with senescent TSEC cells. However, co-culture with resveratrol-treated senescent TSEC cells could partially resume the NO-mediated protective effects of endothelial cells. Furthermore, aged MASH rats showed more severe liver injury, steatosis, fibrosis, and endothelial and microcirculatory dysfunction. In addition, aged MASH patients showed more pronounced liver injury and fibrosis with lower hepatic eNOS, p-eNOS, and SIRT1 protein levels than in young patients. Senescence compromises the protective effects of LSECs against hepatocyte steatosis. In addition, aging aggravates not only liver steatosis and fibrosis but also intensifies LSECs dysfunction in MASH rats. Accordingly aged MASH patients also showed endothelial dysfunction with more severe liver injury and fibrosis.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14502"},"PeriodicalIF":8.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254158","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":"Novel TORC1 inhibitor Ecl1 is regulated by phosphorylation in fission yeast.","authors":"Hokuto Ohtsuka, Sawa Kawai, Yurika Ito, Yuka Kato, Takafumi Shimasaki, Kazuki Imada, Yoko Otsubo, Akira Yamashita, Emi Mishiro-Sato, Keiko Kuwata, Hirofumi Aiba","doi":"10.1111/acel.14450","DOIUrl":"https://doi.org/10.1111/acel.14450","url":null,"abstract":"<p><p>Extender of chronological lifespan 1 (Ecl1) inhibits target of rapamycin complex 1 (TORC1) and is necessary for appropriate cellular responses to various stressors, such as starvation, in fission yeast. However, little is known about the effect of posttranslational modifications on Ecl1 regulation. Thus, we investigated the phosphorylation levels of Ecl1 extracted from yeast under conditions of sulfur or metal starvation. Mass spectrometry analysis revealed that Ecl1 was phosphorylated at Thr7, and the level was decreased by starvation. The phosphorylation-mimetic mutation of Thr7 significantly reduced the effects of Ecl1-induced cellular responses to starvation, suggesting that Ecl1 function was suppressed by Thr7 phosphorylation. By contrast, regardless of starvation exposure, TORC1 was significantly suppressed, even when Thr7 phosphorylation-mimetic Ecl1 was overexpressed. This indicated that Ecl1 suppressed TORC1 regardless of Thr7 phosphorylation. We newly identified that Ecl1 physically interacted with TORC1 subunit RAPTOR (Mip1). Based on these evidences, we propose that, Ecl1 has dual functional modes: quantity-dependent TORC1 inhibition and Thr7 phosphorylation-dependent control of cellular function.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14450"},"PeriodicalIF":8.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254161","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":"Nicotinamide Riboside Supplementation Alleviates Testicular Aging Induced by Disruption of Qprt-Dependent NAD⁺ De Novo Synthesis in Mice.","authors":"Yining Xu, Huan Wang, Hui Li, Chenlu Wei, Zhenye Zhu, Yanqing Zhao, Jiajia Zhu, Min Lei, Yingpu Sun, Qingling Yang","doi":"10.1111/acel.70004","DOIUrl":"https://doi.org/10.1111/acel.70004","url":null,"abstract":"<p><p>Recent studies have shown that disruptions in the nicotinamide adenine dinucleotide (NAD⁺) de novo synthesis pathway accelerate ovarian aging, yet its role in spermatogenesis remains largely unknown. In this study, we investigated the impact of the NAD⁺ de novo synthesis pathway on spermatogenesis by generating Qprt-deficient mice using CRISPR-Cas9 to target quinolinate phosphoribosyl transferase (Qprt), a key enzyme predominantly expressed in spermatocytes. Our results revealed that the deletion of Qprt did not affect NAD⁺ levels or spermatogenesis in the testes of 3-month-old mice. However, from 6 months of age onward, Qprt-deficient mice exhibited significantly reduced NAD⁺ levels in the testes compared to wild-type (WT) controls, along with a notable decrease in germ cell numbers and increased apoptosis. Additionally, these mice demonstrated mitochondrial dysfunction in spermatocytes, impaired progression through prophase I of meiosis, defective double-strand break (DSB) repair, and abnormal meiotic sex chromosome inactivation. Importantly, supplementation with the NAD⁺ precursor nicotinamide riboside (NR) in Qprt-deficient mice restored NAD⁺ levels and rescued the spermatogenic defects. These findings underscore the critical role of NAD⁺ de novo synthesis in maintaining NAD⁺ homeostasis and highlight its importance in meiotic recombination and meiotic sex chromosome inactivation in spermatogenesis.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70004"},"PeriodicalIF":8.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121761","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":"Disease Aggravation With Age in an Experimental Model of Multiple Sclerosis: Role of Immunosenescence.","authors":"María Dema, Herena Eixarch, Arnau Hervera, Mireia Castillo, Luisa M Villar, Xavier Montalban, Carmen Espejo","doi":"10.1111/acel.14491","DOIUrl":"https://doi.org/10.1111/acel.14491","url":null,"abstract":"<p><p>The onset of multiple sclerosis (MS) in older individuals correlates with a higher risk of developing primary progressive MS, faster progression to secondary progressive MS, and increased disability accumulation. This phenomenon can be related to age-related changes in the immune system: with age, the immune system undergoes a process called immunosenescence, characterized by a decline in the function of both the innate and adaptive immune responses. This decline can lead to a decreased ability to control inflammation and repair damaged tissue. Additionally, older individuals often experience a shift toward a more pro-inflammatory state, known as inflammaging, which can exacerbate the progression of neurodegenerative diseases like MS. Therefore, age-related alterations in the immune system could be responsible for the difference in the phenotype of MS observed in older and younger patients. In this study, we investigated the effects of age on the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). Our findings indicate that EAE is more severe in aged mice due to a more inflammatory and neurodegenerative environment in the central nervous system. Age-related changes predominantly affect adaptive immunity, characterized by altered T cell ratios, a pro-inflammatory Th1 response, increased regulatory T cells, exhaustion of T cells, altered B cell antigen presentation, and reduced NK cell maturation and cytotoxicity. Transcriptomic analysis reveals that fewer pathways and transcription factors are activated with age in EAE. These findings allow us to identify potential therapeutic targets specific to elderly MS patients and work on their development in the future.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14491"},"PeriodicalIF":8.0,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077988","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":"Dietary Zinc Limitation Dictates Lifespan and Reproduction Trade-Offs of Drosophila Mothers.","authors":"Sweta Sarmah, Hannah Thi-Hong Hanh Truong, Gawain McColl, Richard Burke, Christen K Mirth, Matthew D W Piper","doi":"10.1111/acel.14498","DOIUrl":"https://doi.org/10.1111/acel.14498","url":null,"abstract":"<p><p>Dietary metal ions significantly influence the lifespan and reproduction of Drosophila females. In this study, we show that not adding any of the metal ions to the diet adversely affects reproduction and lifespan. By contrast, food with no added Zn negatively impacts reproduction but does not adversely affect maternal lifespan, indicating it can dictate resource reallocation between key fitness traits. Specifically, it indicates that female flies stop producing eggs to conserve their body Zn for somatic maintenance. Although these data show that flies can sense varying dietary Zn levels to adjust their physiology, they cannot maximise egg production when faced with a choice between food with no added Zn or food with sufficient Zn to support maximum reproduction. Nonetheless, they can choose to preferentially oviposit on Zn-containing food, perhaps indicating a strategy to assure offspring survival. We also uncovered a role for the white gene in sustaining high levels of egg viability when Zn is diluted in the diet. These insights into the role of dietary metal ions, particularly Zn, point to a central role for these dietary micronutrients to indicate environmental quality and so govern trade-offs between lifespan and reproduction in flies.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14498"},"PeriodicalIF":8.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072932","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":"CAV1 Exacerbates Renal Tubular Epithelial Cell Senescence by Suppressing CaMKK2/AMPK-Mediated Autophagy.","authors":"Liya Sun, Lujun Xu, Tongyue Duan, Yiyun Xi, Zebin Deng, Shilu Luo, Chongbin Liu, Chen Yang, Huafeng Liu, Lin Sun","doi":"10.1111/acel.14501","DOIUrl":"https://doi.org/10.1111/acel.14501","url":null,"abstract":"<p><p>Renal proximal tubular epithelial cell (PTEC) senescence and defective autophagy contribute to kidney aging, but the mechanisms remain unclear. Caveolin-1 (CAV1), a crucial component of cell membrane caveolae, regulates autophagy and is associated with cellular senescence. However, its specific role in kidney aging is poorly understood. In this study, we generated Cav1 gene knockout mice and induced kidney aging using D-galactose (D-gal). The results showed that CAV1 expression increased in the renal cortex of the aging mice, which was accompanied by exacerbated renal interstitial fibrosis, elevated levels of senescence-associated proteins γH2AX and p16^INK4a, and increased β-galactosidase activity. Moreover, autophagy and AMPK phosphorylation in PTECs were reduced. These phenotypes were partially reversed in D-gal-induced Cav1 knockout mice. Similar results were observed in D-gal-induced human proximal tubular epithelial (HK-2) cells, but these effects were blocked when AMPK activation was inhibited. Additionally, in CaMKK2 knockdown HK-2 cells, siCAV1 failed to promote AMPK phosphorylation, whereas this effect persisted when STK11 was knocked down. Besides, we examined the phosphorylation of CaMKK2 and found that siCAV1 increased its activity. Given that CaMKK2 activity is affected by intracellular Ca²⁺, we examined Ca²⁺ levels in HK-2 cells and found that D-gal treatment reduced intracellular Ca²⁺ concentration, but CAV1 knockdown did not alter these levels. Through GST pull-down assays, we demonstrated a direct interaction between CAV1 and CaMKK2. In conclusion, these findings suggest that CAV1 exacerbates renal tubular epithelial cell senescence by directly interacting with CaMKK2, suppressing its activity and AMPK-mediated autophagy via a Ca²⁺-independent pathway.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14501"},"PeriodicalIF":8.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062565","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":"A novel framework to build saliva-based DNA methylation biomarkers: Quantifying systemic chronic inflammation as a case study.","authors":"Lisa J Schmunk, Toby P Call, Daniel L McCartney, Hira Javaid, Waylon J Hastings, Vanja Jovicevic, Dragoljub Kojadinović, Natacha Tomkinson, Eliska Zlamalova, Kirsty C McGee, Jack Sullivan, Archie Campbell, Andrew M McIntosh, Veronika Óvári, Karl Wishart, Christian E Behrens, Emma Stone, Miloš Gavrilov, Rob Thompson, Thomas Jackson, Janet M Lord, Thomas M Stubbs, Riccardo E Marioni, Daniel E Martin-Herranz","doi":"10.1111/acel.14444","DOIUrl":"https://doi.org/10.1111/acel.14444","url":null,"abstract":"<p><p>Accessible and non-invasive biomarkers that measure human ageing processes and the risk of developing age-related disease are paramount in preventative healthcare. Here, we describe a novel framework to train saliva-based DNA methylation (DNAm) biomarkers that are reproducible and biologically interpretable. By leveraging a reliability dataset with replicates across tissues, we demonstrate that it is possible to transfer knowledge from blood DNAm to saliva DNAm data using DNAm proxies of blood proteins (EpiScores). We apply these methods to create a new saliva-based epigenetic clock (InflammAge) that quantifies systemic chronic inflammation (SCI) in humans. Using a large blood DNAm human cohort with linked electronic health records and over 18,000 individuals (Generation Scotland), we demonstrate that InflammAge significantly associates with all-cause mortality, disease outcomes, lifestyle factors, and immunosenescence; in many cases outperforming the widely used SCI biomarker C-reactive protein (CRP). We propose that our biomarker discovery framework and InflammAge will be useful to improve understanding of the molecular mechanisms underpinning human ageing and to assess the impact of gero-protective interventions.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14444"},"PeriodicalIF":8.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062499","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":"Epigenetic modulation rescues neurodevelopmental deficits in Syngap1^+/- mice.","authors":"Akash Kumar Singh, Ila Joshi, Neeharika M N Reddy, Sushmitha S Purushotham, M Eswaramoorthy, Madavan Vasudevan, Sourav Banerjee, James P Clement, Tapas K Kundu","doi":"10.1111/acel.14408","DOIUrl":"https://doi.org/10.1111/acel.14408","url":null,"abstract":"<p><p>SYNGAP1 is a Ras GTPase-activating protein that plays a crucial role during brain development and in synaptic plasticity. Sporadic heterozygous mutations in SYNGAP1 affect social and emotional behaviour observed in intellectual disability (ID) and autism spectrum disorder (ASD). Although neurophysiological deficits have been extensively studied, the epigenetic landscape of SYNGAP1 mutation-mediated intellectual disability is unexplored. Here, we have found that the p300/CBP specific acetylation marks of histones are significantly repressed in the hippocampus of adolescent Syngap1^+/- mice. Additionally, we observed decreased dendritic branching of newly born DCX⁺ neurons in these mice, suggesting altered adult hippocampal neurogenesis. To establish the causal relationship of Syngap1^+/- phenotype and the altered histone acetylation signature we have treated 2-4 months old Syngap1^+/- mice with glucose-derived carbon nanosphere (CSP) conjugated potent small molecule activator (TTK21) of p300/CBP lysine acetyltransferase (CSP-TTK21). The enhancement of the p300/CBP specific acetylation marks of histones by CSP-TTK21 restored synaptic functions, increased dendritic branching of DCX⁺ neurons, enables the capability to reorganise cortical circuits in response to change in the sensory stimuli, and improves behavioural measures in Syngap1^+/- mice that are very closely comparable to wild type littermates. Further, hippocampal RNA-Seq analysis of these mice revealed that the expression of many critical genes such as Adcy1, Ntrk3, Egr1, and Foxj1 which are key regulators of synaptic plasticity and neurogenesis and are well associated with ID/ASD reversed upon CSP-TTK21 treatment. This study could be the first demonstration of the reversal of autistic behaviour and neural wiring upon the modulation of altered epigenetic modification(s).</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14408"},"PeriodicalIF":8.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057563","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":"Physical Exercise Decreases Complement-Mediated Synaptic Loss and Protects Against Cognitive Impairment by Inhibiting Microglial Tmem9-ATP6V0D1 in Alzheimer's Disease.","authors":"Shiyin Li, Mingyue Li, Ge Li, Lili Li, Xiaofeng Yang, Zejie Zuo, Liying Zhang, Xiquan Hu, Xiaofei He","doi":"10.1111/acel.14496","DOIUrl":"https://doi.org/10.1111/acel.14496","url":null,"abstract":"<p><p>Physical exercise is known to slow synaptic neurodegeneration and cognitive aging in Alzheimer's disease (AD). The benefits of physical exercise are related to reduced amyloid beta (Aβ) deposition and increased synaptic plasticity. Yet little is known about the mechanisms that mediate these effects. Here, we show that physical exercise down-regulated the microglial Tmem9 protein, inhibited C1q activation, and decreased C1q-dependent microglial synapse engulfment, eventually ameliorating cognitive impairment in 5xFAD mice. Furthermore, using oAβ cultured-BV2 in vitro, we show that downregulation of microglial Tmem9 was sufficient to restrain complement activity and decrease microglia-mediated synaptic loss, whereas overexpression of microglial Tmem9 tended to promote complement activation and induced synaptic loss, abolishing exercise-associated protection. Finally, we show that microglial Tmem9 contributed to complement activation by regulating ATP6V0D1, a vesicular (H⁺) ATP-dependent proton pump (V-ATPase) subunit that regulates V-ATPase assembly. Together, our results demonstrate that exercise is a potential treatment for AD patients. In an AD mouse model, it decreased the levels of microglial Tmem9 to inhibit the activation of complement, alleviated complement-dependent synaptic loss, and eventually ameliorated emotional and cognitive disorders.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14496"},"PeriodicalIF":8.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051063","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":"Targeting CRM1 for Progeria Syndrome Therapy.","authors":"Adriana Soto-Ponce, Marlon De Ita, Susana Castro-Obregón, Diego Cortez, Yosef Landesman, Jonathan J Magaña, Susana Gonzalo, Tania Zavaleta, Angelica Soberano-Nieto, Juan Unzueta, Isabel Arrieta-Cruz, Porfirio Nava, Aurora Candelario-Martínez, Ian García-Aguirre, Bulmaro Cisneros","doi":"10.1111/acel.14495","DOIUrl":"https://doi.org/10.1111/acel.14495","url":null,"abstract":"<p><p>Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by progerin, a mutant variant of lamin A. Progerin anchors aberrantly to the nuclear envelope disrupting a plethora of cellular processes, which in turn elicits senescence. We previously showed that the chromosomal region maintenance 1 (CRM1)-driven nuclear export pathway is abnormally enhanced in patient-derived fibroblasts, due to overexpression of CRM1. Interestingly, pharmacological inhibition of CRM1 using leptomycin B rescues the senescent phenotype of HGPS fibroblasts, delineating CRM1 as a potential therapeutic target against HGPS. As a proof of concept, we analyzed the beneficial effects of pharmacologically modulating CRM1 in dermal fibroblasts from HGPS patients and the LMNA^G609G/G609G mouse, using the first-in-class selective inhibitor of CRM1 termed selinexor. Remarkably, treatment of HGPS fibroblasts with selinexor mitigated senescence and promoted progerin clearance via autophagy, while at the transcriptional level restored the expression of numerous differentially-expressed genes and rescued cellular processes linked to aging. In vivo, oral administration of selinexor to the progeric mouse resulted in decreased progerin immunostaining in the liver and aorta, decreased progerin levels in most liver, lung and kidney samples analyzed by immunoblotting, and improved aortic histopathology. Collectively our data indicate that selinexor exerts its geroprotective action by at least two mechanisms: normalizing the nucleocytoplasmic partition of proteins with a downstream effect on the aging-associated transcriptome and decreasing progerin levels. Further investigation of the overall effect of selinexor on Lmna^G609G/G609G mouse physiology, with emphasis in cardiovascular function is warranted, to determine its therapeutic utility for HGPS and aging-associated disorders characterized by CRM1 overactivity.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14495"},"PeriodicalIF":8.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050941","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}