Aging and Disease最新文献_第9页

Melatonin in Circadian Rhythm and Brain Health: Neuroprotective Effects and Therapeutic Potential. 褪黑素在昼夜节律和大脑健康中的作用：神经保护作用和治疗潜力。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-19 DOI: 10.14336/AD.2026.0119

Yuxiao Feng, Yanpo Si, Xin Pang, Shuying Feng, Yuewen Zhang, Shujuan Xue, Tao Guo

引用次数: 0

Harnessing Neuronal Autophagy: Bridging Mechanistic Breakthroughs to Therapeutic Interventions. 利用神经元自噬：连接机制突破到治疗干预。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-19 DOI: 10.14336/AD.2025.0804

Nuzhat Ahsan, Farheen Badrealam Khan, Jhinuk Basu, Mohd Shariq, Nida Zaidi, Rizwan Hasan Khan, Reshmi Raj, Mohammed Akli Ayoub, Avadhesha Surolia, Ghulam Md Ashraf

{"title":"Harnessing Neuronal Autophagy: Bridging Mechanistic Breakthroughs to Therapeutic Interventions.","authors":"Nuzhat Ahsan, Farheen Badrealam Khan, Jhinuk Basu, Mohd Shariq, Nida Zaidi, Rizwan Hasan Khan, Reshmi Raj, Mohammed Akli Ayoub, Avadhesha Surolia, Ghulam Md Ashraf","doi":"10.14336/AD.2025.0804","DOIUrl":"https://doi.org/10.14336/AD.2025.0804","url":null,"abstract":"Autophagy, an essential cellular process that degrades and recycles misfolded proteins, damaged organelles, and intracellular pathogens, is vital for neurons due to their limited capacity for apoptosis. Dysregulation of autophagy and lysosomal pathways is closely linked to the onset and progression of major neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In this manuscript, we offer a thorough examination of the molecular mechanisms that regulate autophagy, emphasizing both bulk and selective autophagy pathways and their roles in maintaining neuronal homeostasis. Genetic mutations in autophagy-related genes and endolysosomal genes are identified as significant risk factors, and the pathological roles of protein aggregation and mitochondrial dysfunction are also discussed. The therapeutic restoration of autophagic function represents a promising strategy for alleviating neurodegeneration. This manuscript examines potential interventions, including small molecules, gene therapy, and natural compounds, that enhance autophagic flux and facilitate protein clearance. Furthermore, the translational potential was underscored by including ongoing clinical trials that target autophagy pathways. This review artcile emphasizes the essential role of autophagy in neuronal health and disease, providing a framework for utilizing autophagic mechanisms to develop targeted therapeutic strategies for NDDs.","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cellular Senescence in the Absence of Galactic Cosmic-Ray Muons. 在没有银河宇宙射线μ子的情况下细胞衰老。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-18 DOI: 10.14336/AD.2026.0025

Àngela Llop-Hernández, Júlia López, Sara Verdura, Rebecca Hernández-Antolín, Laura Cid-Barrio, Carlos Peña-Garay, Tomás Alarcón, Elisabet Cuyàs, Javier A Menendez

{"title":"Cellular Senescence in the Absence of Galactic Cosmic-Ray Muons.","authors":"Àngela Llop-Hernández, Júlia López, Sara Verdura, Rebecca Hernández-Antolín, Laura Cid-Barrio, Carlos Peña-Garay, Tomás Alarcón, Elisabet Cuyàs, Javier A Menendez","doi":"10.14336/AD.2026.0025","DOIUrl":"https://doi.org/10.14336/AD.2026.0025","url":null,"abstract":"Cellular senescence is a stress response that prevents the proliferation of damaged cells. As senescence has evolved in the near-surface biosphere, where cosmic background radiation (CBR) continuously delivers a low flux of highly penetrating muon particles, we investigated whether this persistent abiotic stress contributes to senescence thresholding. At the Canfranc Deep Underground Laboratory, an astrophysical facility located 800 meters beneath granite rock in the Spanish Pyrenees (~2,450 meters of water-equivalent depth), cosmic muons are suppressed by five orders of magnitude. There, we examined the senescence-induction dynamics in human cancer cells exposed to G0/G1- or G2/M-targeting chemotherapeutics and compared them to cells in adjacent, above-ground conditions with natural CBR. Muon depletion significantly reduced the acquisition of the senescence-associated β-gal-positive phenotype under conditions favoring a G0/G1 arrest with the CDK4/6 inhibitor palbociclib. SA-β-gal-positive states driven by G2/M arrest in response to the mitotic kinase inhibitor alisertib and the DNA-damaging radiomimetic bleomycin were insensitive to muon suppression. While the SENCAN classifier, which uses RNA-seq data to determine whether cell samples are senescent, and the senescence-associated secretory phenotype profiles were largely unaffected by the absence of cosmic-ray muons, muon depletion caused small variations at a transcriptome-wide level in the two pathways to senescence. Our hypothesis-generating study suggests that muons might act as abiotic signal-to-noise calibrators that facilitate the consolidation of senescence trajectories specifically associated with G0/G1 withdrawal. Our exploratory findings shed light on how life incorporated CBR evolutionarily to sense and respond to cellular damage, which could inform senescence operability in low-muon extraterrestrial habitats.","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Dickkopf Protein Family in Non-Neoplastic Disorders: Emerging Roles and Therapeutic Targeting. Dickkopf蛋白家族在非肿瘤性疾病中的作用和治疗靶向。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-17 DOI: 10.14336/AD.2025.1506

Juju Zhou, Xiaoqian Zhu, Weihan Chen, Junjuan Tan, Liwei Hong, Lingya Yang, Yonglin Liu, Tiantian Zhai, Kai Chen

{"title":"The Dickkopf Protein Family in Non-Neoplastic Disorders: Emerging Roles and Therapeutic Targeting.","authors":"Juju Zhou, Xiaoqian Zhu, Weihan Chen, Junjuan Tan, Liwei Hong, Lingya Yang, Yonglin Liu, Tiantian Zhai, Kai Chen","doi":"10.14336/AD.2025.1506","DOIUrl":"https://doi.org/10.14336/AD.2025.1506","url":null,"abstract":"The Dickkopf (DKK) family of secreted glycoproteins, comprising DKK1-4, serves as a pivotal regulator of the Wnt signaling pathway. Acting as canonical antagonists of the Wnt/β-catenin cascade, these proteins are indispensable for essential biological processes such as cellular proliferation, differentiation, development, and tissue homeostasis. In recent years, aberrant expressions of DKK proteins has been extensively documented in multiple cancers. Simultaneously, their pathophysiological roles and clinical relevance in non-oncological diseases have garnered growing attention. Disorders such as osteoporosis and arthritis, chronic kidney disease (CKD), myocardial injury, as well as neurodegenerative and dermatological conditions, including Alzheimer's disease (AD) and alopecia, have all been linked to DKK family members. These broad associations emphasize their substantial potential as diagnostic biomarkers and as promising therapeutic targets. This review provides a systematic synthesis of recent research within the past three years on the roles of the DKK protein family in diverse non-oncological diseases, further examining their prospective applications as biomarkers and therapeutic targets while addressing related challenges, with the aim of offering novel insights into diagnosis and treatment.","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Difference between Biological Age and Chronological Age Predicts Mortality and Hospitalization in a Longitudinal Adult Cohort. 在纵向成人队列中，生物年龄和实足年龄的差异预测死亡率和住院率。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-17 DOI: 10.14336/AD.2026.0260

Abigail Goshen, Evelyne Bischof, Edward H Livingston, Daphna Katz, Chaim Haber, Nitsan Halabi, Michal Cohen Shelly, Shlomo Segev, Yael Mintz, Tzipora Strauss

{"title":"Difference between Biological Age and Chronological Age Predicts Mortality and Hospitalization in a Longitudinal Adult Cohort.","authors":"Abigail Goshen, Evelyne Bischof, Edward H Livingston, Daphna Katz, Chaim Haber, Nitsan Halabi, Michal Cohen Shelly, Shlomo Segev, Yael Mintz, Tzipora Strauss","doi":"10.14336/AD.2026.0260","DOIUrl":"https://doi.org/10.14336/AD.2026.0260","url":null,"abstract":"Biological age (BA) reflects overall health status and may deviate from chronological age (CA). Whether the magnitude of this difference (Agediff) independently predicts hospitalization and mortality remains unknown. Retrospective longitudinal cohort of 2,597 adults (27.5% women), aged 21-92 years, participating in an executive screening program at Sheba Medical Center, Israel, contributing 6,772 clinical encounters between 2006 and 2020, mean follow-up 9.2 (2.2) years. BA was estimated to use a previously established deep-learning model trained on routine clinical laboratory tests. Bayesian time-dependent Cox models evaluated associations between Agediff and all-cause mortality, and negative-binomial models were applied to hospitalizations, adjusting for age, sex, BMI, smoking, and baseline comorbidities. The Agediff associated with a hazard ratio (HR) of 1.5 for mortality was determined for each chronological age, and Agediff ×age interaction was tested. Each 1-year increase in Agediff was associated with a 15% higher mortality hazard (HR 1.15, 95% CI 1.10-1.21) and a 6% higher hospitalization rate (incidence rate ratio 1.06, 95% CI 1.03-1.09). The Agediff ×age interaction was not significant (p = 0.56). The Agediff required to reach HR = 1.5 decreased with chronological age, from approximately 5 years at age 40 to 3 years at age 80. Agediff ≥3 years was associated with a clinically significant increase in mortality. In this cohort, a BA estimated from routine laboratory results exceeding CA by 3 or more years was associated with increased hospitalization and mortality risk, suggesting potential utility for risk stratification in clinical settings.","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LRRC8A in Aging and Aging-Related Diseases: Emerging Evidence and Therapeutic Potential. LRRC8A在衰老和衰老相关疾病中的作用：新证据和治疗潜力。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-16 DOI: 10.14336/AD.2026.0301

Yuman Wang, Teding Chang, Anding Liu, Cuntai Zhang

{"title":"LRRC8A in Aging and Aging-Related Diseases: Emerging Evidence and Therapeutic Potential.","authors":"Yuman Wang, Teding Chang, Anding Liu, Cuntai Zhang","doi":"10.14336/AD.2026.0301","DOIUrl":"https://doi.org/10.14336/AD.2026.0301","url":null,"abstract":"The aging process is a major risk factor for numerous chronic diseases, and the progressive increase in global life expectancy has intensified the need to understand the molecular mechanisms underlying aging and age-related diseases. Volume-regulated anion channel (VRAC) plays a fundamental role in maintaining cellular homeostasis, among which leucine-rich repeat-containing protein 8A (LRRC8A) serves as the essential core subunit. Emerging evidence indicates that LRRC8A participates in diverse biological processes, including cell volume regulation, redox balance, metabolic homeostasis, inflammation and immune responses. Based on these mechanisms, LRRC8A may contribute to multiple aging-related processes, including inflammaging, immunosenescence and cellular senescence. Dysregulation of LRRC8A has been implicated in a variety of pathological conditions, including cardiovascular, neurodegenerative and metabolic diseases, many of which are strongly associated with aging. In this review, we summarize the current understanding of LRRC8A structure, biological functions, and signaling mechanisms, and discuss its emerging roles in aging and aging-related diseases. Furthermore, we discuss the therapeutic implications and translational constraints of LRRC8A modulation, emphasizing the need for tissue-specific, context-dependent, and aging-specific validation before clinical application.","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deep Venous Perivascular Space Dysfunction Reflects Glymphatic Aging and Predicts Cognitive Vulnerability: In Vivo Human Evidence. 深静脉血管周围空间功能障碍反映淋巴老化并预测认知脆弱性：体内人类证据。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-15 DOI: 10.14336/AD.2025.1587

Kemeng Zhang, Ying Zhou, Yifei Li, Xin Huang, Mengmeng Fang, Kai Wei, Min Lou

{"title":"Deep Venous Perivascular Space Dysfunction Reflects Glymphatic Aging and Predicts Cognitive Vulnerability: In Vivo Human Evidence.","authors":"Kemeng Zhang, Ying Zhou, Yifei Li, Xin Huang, Mengmeng Fang, Kai Wei, Min Lou","doi":"10.14336/AD.2025.1587","DOIUrl":"https://doi.org/10.14336/AD.2025.1587","url":null,"abstract":"Impaired glymphatic clearance has been recognized as a fundamental mechanism of cognitive decline. While models suggest cerebrospinal fluid influx along arterial perivascular spaces (aPVS) and efflux along venous PVS (vPVS), their differential roles in humans are unclear. We aimed to visualize directional glymphatic flow in vivo, classify human PVS functionally and determine their associations with cognition. This study included 91 patients undergoing intrathecal gadodiamide with serial MRI at baseline, 4.5 hours, 15 hours and 39 hours post-injection. PVS showing early (4.5h) and delayed (39h) enhancement peaks were defined as aPVS and vPVS, respectively. Among 742 basal ganglia (BG) and 1380 centrum semiovale (CSO) PVS analyzed, 10.4% and 21.6% were aPVS, while 62.7% and 52.0% were vPVS, respectively. BG-vPVS burden correlated with age (r=0.275, p<0.001) and hypertension. Among 60 patients with cognitive assessment (telephone Montreal Cognitive Assessment, T-MoCA) data, only BG-vPVS burden independently correlated with lower scores after adjusting for age and education (β=-0.16, p=0.041). This study provided direct in vivo MRI evidence of glymphatic flow within human PVS. We introduced a novel functional classification method to differentiate arterial from venous PVS, finding their different role in cognitive impairment, which may represent a potential target for therapeutic intervention.","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Impact of Aging on Hemorrhagic Transformation after Recanalization for Acute Ischemic Stroke: From Mechanisms to Targeted Treatments. 衰老对急性缺血性脑卒中再通后出血转化的影响：从机制到靶向治疗。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-14 DOI: 10.14336/AD.2026.0143

Bo Wu, Yuhong Li, Zirui Chen, Qinhong Li, Rongsu Huang, Dongyun Zhang, Jichao Yuan, Yujie Chen, Nan Wu

{"title":"The Impact of Aging on Hemorrhagic Transformation after Recanalization for Acute Ischemic Stroke: From Mechanisms to Targeted Treatments.","authors":"Bo Wu, Yuhong Li, Zirui Chen, Qinhong Li, Rongsu Huang, Dongyun Zhang, Jichao Yuan, Yujie Chen, Nan Wu","doi":"10.14336/AD.2026.0143","DOIUrl":"https://doi.org/10.14336/AD.2026.0143","url":null,"abstract":"Hemorrhagic transformation after recanalization represents a common and life-threatening complication of acute ischemic stroke, yet its intimate association with aging remains incompletely elucidated. This review comprehensively summarizes the interplay between aging and post-recanalization hemorrhagic transformation, ranging from underlying molecular and pathological mechanisms to novel targeted therapeutic strategies. We mainly elaborate three core mechanistic dimensions, including aging-induced blood-brain barrier disruption, impairment of vascular structural integrity, and aggravated ischemia-reperfusion injury, which synergistically elevate the susceptibility to hemorrhagic transformation. Beyond general preventive regimens after stroke, we further highlight aging-targeted intervention approaches, covering MMP inhibition, BBB protection, oxidative stress modulation, RAS regulation, senomorphic and senolytic therapies, as well as lifestyle modification, to provide mechanistic insights and translational references for reducing hemorrhagic transformation risk. This review aims to deepen the understanding of aging-related hemorrhagic transformation and help optimize clinical management and long-term prognosis of acute ischemic stroke patients.","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Serum Calcification Propensity and CPP2 Size - Deranged Mineral Buffering and The Risk of Mortality in Older Adults. 老年人血清钙化倾向、CPP2大小紊乱的矿物质缓冲和死亡风险。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-13 DOI: 10.14336/AD.2025.1335

Mirjam Schuchardt, Nina Mielke, Muhammad Helmi Barghouth, Jaqueline Herrmann, Ioana Alesutan, Andreas Pasch, Markus van der Giet, Kai-Uwe Eckardt, Elke Schaeffner, Natalie Ebert, Markus Tölle, Jakob Voelkl

{"title":"Serum Calcification Propensity and CPP2 Size - Deranged Mineral Buffering and The Risk of Mortality in Older Adults.","authors":"Mirjam Schuchardt, Nina Mielke, Muhammad Helmi Barghouth, Jaqueline Herrmann, Ioana Alesutan, Andreas Pasch, Markus van der Giet, Kai-Uwe Eckardt, Elke Schaeffner, Natalie Ebert, Markus Tölle, Jakob Voelkl","doi":"10.14336/AD.2025.1335","DOIUrl":"https://doi.org/10.14336/AD.2025.1335","url":null,"abstract":"Ageing is associated with increased vascular calcification. However, the parallels with chronic kidney disease are unclear, where secondary calciprotein particles (CPP2) are increasingly formed due to insufficient mineral buffering. CPP2 induce vascular dysfunction as well as calcification and thereby could increase mortality risk. This study aimed to assess whether indicators of deranged mineral buffering are associated with mortality in older adults. Serum calcification propensity (T50) and hydrodynamic radius of CPP2 were assessed in 1,566 participants of the population-based Berlin Initiative (cohort) Study (BIS) of older adults with a mean age of 81.8 years. The associations with all-cause and cardiovascular mortality were assessed using multivariable Cox regression models, adjusted for cardiovascular risk factors. During a median follow-up of 9.1 years, 814 participants died, of whom 350 died from a cardiovascular cause. An increase of CPP2 size was associated with increased Hazard Ratios (HR) for all-cause mortality (age and sex adjusted HR [95% CI], 1.19 [1.10-1.28]; fully adjusted for other confounders HR [95% CI], 1.15 [1.06-1.24]) and cardiovascular mortality when age and sex adjusted (HR [95% CI], 1.17 [1.05-1.31]) but not when fully adjusted (HR [95% CI], 1.11 [0.98-1.25]). Furthermore, each 60 min decrease of T50 was associated with increased HR for all-cause mortality when age and sex adjusted (HR [95% CI], 1.10 [1.03-1.17]) but not when fully adjusted (HR [95% CI], 1.06 [1.00-1.14]), and without clear association with cardiovascular mortality (fully adjusted, HR [95% CI], 0.98 [0.89-1.08]). Disturbed mineral buffering, as inferred from increased CPP2 size, may be a novel and independent risk factor for mortality in older adults.","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

circHIPK3 Sustains Ribosome Biogenesis and Protects Against Cardiac Aging by Stabilizing Ncl mRNA and Supporting its LLPS. circHIPK3通过稳定Ncl mRNA和支持其LLPS来维持核糖体生物发生并防止心脏老化。

IF 6.9 2区医学

Aging and Disease Pub Date : 2026-05-12 DOI: 10.14336/AD.2026.0142

Huiling Zhang, Tonggan Lu, Xinlan Lv, Yu Zhang, Ao Li, Zirui Zhao, Han Zhou, Bin Liu, Yan Xu, Yangxin Li

{"title":"circHIPK3 Sustains Ribosome Biogenesis and Protects Against Cardiac Aging by Stabilizing Ncl mRNA and Supporting its LLPS.","authors":"Huiling Zhang, Tonggan Lu, Xinlan Lv, Yu Zhang, Ao Li, Zirui Zhao, Han Zhou, Bin Liu, Yan Xu, Yangxin Li","doi":"10.14336/AD.2026.0142","DOIUrl":"https://doi.org/10.14336/AD.2026.0142","url":null,"abstract":"To investigate the molecular mechanism of cardiac aging and identify novel regulatory targets, we focused on circular RNA HIPK3 (circHIPK3) and its role in regulating Nucleolin (Ncl)-mediated biological processes. circHIPK3 expression was progressively downregulated with age in mouse hearts. We generated cardiomyocyte-specific circHIPK3 knockout (CKO) mice, and found that these mice exhibited cardiac aging phenotypes, cardiac dysfunction, hypertrophy, and fibrosis. Mechanistically, circHIPK3 is directly bound to the 5' UTR of Ncl mRNA to enhance its stability, thereby preserving Ncl protein levels and supporting Ncl-mediated liquid-liquid phase separation (LLPS), a critical process for efficient ribosome biogenesis. circHIPK3 deficiency is accompanied by altered Ncl LLPS dynamics, reduced ribosomal RNA synthesis and ribosomal protein expression, and impaired de novo ribosome production. Conversely, circHIPK3 overexpression restored Ncl expression, rescued LLPS and ribosome biogenesis defects, and alleviated aging-related cardiac phenotypes in vitro and in vivo. In conclusion, we identify a novel \"circHIPK3-Ncl-ribosome biogenesis\" axis that protects against cardiac aging through post-transcriptional and biophysical regulation. circHIPK3 represents a potential biomarker and warrants further investigation as a therapeutic candidate for age-related cardiovascular dysfunction, providing new insights into the intersection of non-coding RNA function, ribosome biogenesis and organ aging.","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0