Aging Cell最新文献

{"title":"Vitamin D Deficiency, Supplementation, and Aging-Related Morbidity and Mortality Across Two Longitudinal Population Cohorts.","authors":"Ariel Israel, Abraham Weizman, Sarah Israel, Shai Ashkenazi, Eytan Ruppin, Eli Magen, Eugene Merzon, Shlomo Vinker","doi":"10.1111/acel.70752","DOIUrl":"10.1111/acel.70752","url":null,"abstract":"<p><p>Vitamin D deficiency has been implicated in biological processes linked to aging and organismal resilience, yet its relationship to long-term systemic aging trajectories remains incompletely characterized. We analyzed longitudinal electronic health record data from two large healthcare systems: Leumit Health Services (LHS), a nationwide Israeli health organization, and TriNetX, a federated US research network. We examined more than 1.67 million serum 25-hydroxyvitamin D [25(OH)D] measurements from over 468,500 adults in LHS (2009-2020). Longitudinal matched analyses compared severe deficiency (< 10 ng/mL) with sufficiency (> 30 ng/mL) in LHS and were externally validated in 223,175 propensity score-matched TriNetX pairs; matched cohorts were approximately 54 years old, 65%-67% female, and followed for up to 10 years. In both populations, severe deficiency was associated with increased risks across multiple aging-related outcomes. All-cause mortality was higher in LHS (adjusted HR 2.57, 95% CI 2.38-2.79) and TriNetX (HR 1.59, 1.55-1.63). To assess modifiability, we modeled vitamin D supplementation longitudinally using pharmacy-dispensed purchases calibrated to predict serum 25(OH)D changes over time. Supplementation was independently associated with dose-dependent reductions across mortality and multiple aging-related outcomes; for > 10 ng/mL-equivalent supplementation, mortality HR was 0.72 (0.68-0.76), while showing no corresponding association for skin malignancy. To strengthen causal interpretation, we additionally implemented inverse-probability-of-treatment-weighted marginal structural Cox models for mortality, which yielded results consistent with conventional adjusted models. Together, these findings support severe vitamin D deficiency as an important and potentially modifiable determinant of systemic aging vulnerability and age-related multimorbidity in human populations.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70752"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134376","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":"Targeting Ero1L by Parthenolide Alleviates Cellular Senescence and Fibrosis of Localized Scleroderma by Regulating Mitochondria-Associated Endoplasmic Reticulum Membranes Stabilization.","authors":"Fei Wang, Ru Xing, Meijuan Xie, Yimin Qin, Yunchao Zhang, Dan Cao, Gu He, Xiaoyan Lyu","doi":"10.1111/acel.70738","DOIUrl":"10.1111/acel.70738","url":null,"abstract":"<p><p>Mitochondrial dysfunction drives scleroderma pathogenesis. The mitochondria-associated endoplasmic reticulum membrane (MAM) regulates mitochondrial function. Parthenolide (PTL) has protective effects on mitochondria. However, its specific role and mechanisms in localized scleroderma (LoS) remain unclear. This study investigates whether PTL reduces senescence and skin fibrosis by stabilizing MAM in LoS and examines the protective effects of a synthesized thermosensitive controlled-release hydrogel (F127@PLGA@PTL) against LoS. We employed transmission electron microscopy (TEM) to observe MAM abnormalities in LoS skin lesions. Other multiple molecular biology experiments were conducted to investigate how PTL protects against LoS in TGF-β-induced human dermal fibroblasts (HDFs) and a murine model of LoS. RNA sequencing, molecular docking-based inverse virtual screening, and surface plasmon resonance (SPR) were used to find possible targets of PTL. Emulsification-volatilization was used to prepare the PTL-loaded PLGA nanoparticles. MAM's calcium ion transport function is enhanced, and its quantity increases in LoS. PTL can ameliorate senescence and fibrosis in TGF-β-induced HDF cells and the bleomycin-induced LoS model by regulating the IP3R1/Grp75/VDAC1 complex and repairing mitochondrial damage. Notably, mechanistically, this protective effect was mediated through Ero1L suppression, with ARG-449 identified as the critical residue for PTL-Ero1L binding. Ero1L overexpression reversed the protective effects of PTL. Additionally, Ero1L knockdown also exhibits anti-senescence and antifibrotic effects on TGF-β-induced HDFs. Furthermore, F127@PLGA@PTL demonstrates excellent sustained-release properties and significant therapeutic efficacy in the mouse model of LoS. The study demonstrates that PTL alleviates fibrosis of LoS by regulating Ero1L-mediated MAM stabilization.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70738"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079243","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":"Systemic Loss of Chromosome Y Associates With Age-Related Ophthalmic Diseases in Middle-Aged Men: A Longitudinal Multi-Omic Study.","authors":"Tianhao Chen, Zhaoyu Xiang, Zhe Zhang, Bingqing Sun, Xuan Ding, Liyin Wang, Yunqian Yao, Zhuotong Wu, Siyang Liu, Yuan Lei, Xingtao Zhou, Jing Zhao","doi":"10.1111/acel.70775","DOIUrl":"10.1111/acel.70775","url":null,"abstract":"<p><p>Maintaining health during global population aging represents a critical challenge, where mosaic loss of chromosome Y (LOY) in the hematopoietic system surfaces as a prevalent somatic mutation in aging men. However, its longitudinal impact on sensory organ degeneration remains insufficiently characterized. Analyzing 223,051 male participants from the UK Biobank, we demonstrated that LOY uniquely and independently predicted an increased risk of incident age-related macular degeneration (AMD) (Hazard Ratio = 0.611, 95% Confidence Interval: 0.397-0.942). Restricted cubic splines identified a critical risk escalation threshold at -0.17 for median log R ratio. Over a 15-year preclinical window, Olink plasma proteomics identified 41 prioritized proteins demonstrating divergent nonlinear kinetic profiles leading up to clinical diagnosis; notably, the elastin-degrading matrix metalloproteinase-12 deviated significantly 12 years prior to endpoint. Integrating single-cell RNA sequencing datasets of peripheral blood and choroidal tissues validated that CD16⁺ circulatory monocytes and resident macrophages exhibited peak LOY frequencies. Furthermore, Y-deficient myeloid cells manifested a pro-inflammatory phenotype with cell-type-specific upregulation of IFI30 and CKB, bridging single-cell transcriptional activation with systemic proteomic dysregulation. Causal mediation analysis confirmed that peripheral monocyte counts significantly mediated the LOY-associated degenerative risk. Utilizing these prioritized proteomic signatures, a LightGBM machine learning framework achieved robust predictive performance for 5-year incident risk (AUC = 0.734). Collectively, these findings establish a distinct somatic mutation-immune-retinal axis, positioning systemic clonal mosaicism not merely as a marker of biological senescence but as an upstream driver of site-specific organ degeneration, offering novel strategies for early risk stratification and precision intervention in aging-related diseases.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70775"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219610","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":"Aging Affects Pancreatic α-Cell Function and Promotes Hyperglucagonemia: Implications in Age-Associated Diabetes.","authors":"Eva Tudurí, Lucía Almagro, Ana Ojeda-Rodríguez, Raquel Pascua-Maestro, Henver S Brunetta, Sergi Soriano, Alejandro López-Moreno, Talía Boronat-Belda, Sergio Velasco-Avilés, Joel Alves da Silva Junior, Manuel Castellano-Muñoz, Alex Rafacho, Irene Cózar-Castellano, Ángel Nadal, Paloma Alonso-Magdalena, Beatriz Merino, José López-Miranda, Ivan Quesada","doi":"10.1111/acel.70753","DOIUrl":"10.1111/acel.70753","url":null,"abstract":"<p><p>Aging is a major risk factor in the development of type 2 diabetes mellitus (T2DM). With age, pancreatic β-cells undergo functional and cell identity changes that can compromise insulin secretion, thereby contributing to impaired glucose tolerance and T2DM. However, glucose homeostasis also depends on pancreatic α-cells. Excessive plasma glucagon levels, along with impaired regulation of α-cell secretion, are involved in the pathophysiology of T2DM. Despite their importance, the effects of aging on α-cells have been overlooked. In the present study, we analyzed pancreatic α-cells in aged mice with normal insulin sensitivity and in those with peripheral insulin resistance. Regardless of insulin sensitivity, aged mice exhibited hyperglucagonemia and increased glucagon release. Ex vivo, these alterations were associated with increased α-cell mass, higher glucagon content, impaired suppression of glucagon secretion, and endoplasmic reticulum stress. Furthermore, aged mice showed remodeling of islet cellular composition and changes in the spatial organization of α-cells within the islet. Additionally, moderate alterations in α-cell identity were noted. While most of these alterations were already present in aged mice with normal insulin sensitivity, they were generally more pronounced with insulin resistance. Examination of the CORDIOPREV clinical study revealed the presence of hyperglucagonemia in older adults with insulin resistance. Additionally, an increased risk of developing T2DM was also found in older people with higher plasma glucagon levels. The findings described here indicate that aging affects the biology of α-cells and glucagon, positioning them as active players in impaired glucose tolerance and diabetes associated with aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70753"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101575","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":"Birthweight and Breastfeeding Shape Patterns of Biological Aging Across Adult Organs.","authors":"Wenming Wei, Xin Qi, Bolun Cheng, Boyue Zhao, Dan He, Jingni Hui, Jin Feng, Shiqiang Cheng, Xuena Yang, Chuyu Pan, Yifan Gou, Yan Wen, Huan Liu, Yumeng Jia, Li Liu, Feng Zhang","doi":"10.1111/acel.70762","DOIUrl":"10.1111/acel.70762","url":null,"abstract":"<p><p>Early-life nutrition may influence long-term health, but its impact on organ-specific biological aging is unclear. We investigated associations of birthweight and breastfeeding with multi-organ aging and potential mediating pathways in adulthood. Using UK Biobank data, we examined associations of retrospectively reported birthweight (n = 21,446) and breastfeeding history (n = 29,713) with 19 proteomics-derived aging indices, comprising 18 organ-specific indices and one composite index. Multivariable linear regression assessed individual and joint associations, effect modification by sex and socioeconomic factors, and mediation by allostatic load (AL) and C-reactive protein (CRP). Higher birthweight was inversely associated with aging across 11 organ systems (all FDR-adjusted p < 0.05), with strongest associations in the intestine (β = -0.069), esophagus (β = -0.055), and stomach (β = -0.053). Breastfeeding exposure was associated with slower aging of the intestine (β = -0.047) and adrenal gland (β = -0.030), but modestly faster thyroid aging (β = 0.033). The combination of higher birthweight and breastfeeding was associated with favorable aging profiles, particularly in the intestine (β = -0.13), stomach (β = -0.09), and kidney (β = -0.08). Associations were stronger among females and socioeconomically advantaged or healthier-behavior subgroups. AL mediated up to 35.3% of the birthweight-aging association, whereas CRP showed minimal mediation. Higher birthweight and breastfeeding, particularly in combination, produce the most favorable profiles of multi-organ biological aging in adulthood, with AL partially mediating these effects. These findings provide novel evidence that prenatal and postnatal nutrition leave enduring, system-wide imprints on adult aging trajectories.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70762"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134176","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":"When to Trust Epigenetic Clocks: Avoiding False Positives in Aging Interventions.","authors":"Daniel S Borrus, Raghav Sehgal, Jenel Fraij Armstrong, Jessica Kasamoto, John Gonzalez, Albert Higgins-Chen","doi":"10.1111/acel.70756","DOIUrl":"10.1111/acel.70756","url":null,"abstract":"<p><p>Epigenetic clocks have emerged as potential biomarkers of aging due to their association with morbidity and mortality. They have recently gained traction as outcome measurements for anti-aging interventions. However, as the number of new epigenetic clocks continues to grow, different clocks may not agree on the effect of an intervention. This raises the question of when researchers can trust epigenetic clock results. In this study, we find that when extending previously published single-clock intervention studies to include additional clock models, no additional clocks reach statistical significance. We then analyze clock behavior across positive control datasets (age-accelerating events) to propose three criteria that increase confidence in a result: (1) reliable PC-based clocks respond, (2) mortality-trained or pace-of-aging clocks respond, and (3) multiple clocks respond in the same direction. To explain why genuine effects would appear across multiple clocks, we perform a simulation study to demonstrate how reliable clocks are more sensitive to true effects, and use longitudinal control datasets to show that reliable clock changes are correlated with each other. We then show examples of interventions that do satisfy these criteria. These findings provide a framework for interpreting epigenetic clock results in anti-aging intervention studies, and suggest that some previously published single-clock findings may warrant reexamination.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70756"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134412","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":"Direct Pharmacological Activation of AMPK Extends Lifespan in Yeast, Worms and Flies.","authors":"Eliano Dos Santos, Marie Blickling, Fiona C Leiper, John-Patrick Alao, Claudia Lennicke, Andrea Foley, Jon R Wilson, Steven J Gamblin, Bénédicte Chazaud, Giovanna Lollo, Rémi Mounier, Gaëtan Juban, Charalampos Rallis, David Carling, Filipe Cabreiro, Helena M Cochemé","doi":"10.1111/acel.70721","DOIUrl":"10.1111/acel.70721","url":null,"abstract":"<p><p>AMP-activated protein kinase (AMPK) is a key evolutionarily conserved sensor of energy homeostasis and plays a central role in metabolic health and disease. AMPK has also been implicated in ageing; however, most in vivo drug studies rely on the use of indirect activators, such as metformin, which have complex modes-of-action, therefore making conclusions on the specific role of AMPK more challenging. Here, we demonstrate that direct activation of AMPK with the compound 991 extends lifespan in Drosophila melanogaster, Caenorhabditis elegans and Schizosaccharomyces pombe. In mice, 991 treatment induces a pro-longevity proteomic profile, highlighting the potential for translation to mammals. Overall, our study provides important proof-of-principle for AMPK as a pharmacological target with longevity benefits.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70721"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079263","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":"SIRT6 Activation Improves Intervertebral Disc Health in the Aging Spine.","authors":"Pranay Ramteke, Bahiyah Watson, Sanjana Jagannath, Sarah E Bell, Mallory Toci, Olivia Ottone, Qinglin Wu, Oliver Abinader, Ramkrishna Mitra, John A Collins, Ruteja A Barve, Makarand V Risbud","doi":"10.1111/acel.70709","DOIUrl":"https://doi.org/10.1111/acel.70709","url":null,"abstract":"<p><p>Aging is a critical risk factor for intervertebral disc degeneration, a major contributor to chronic low back pain. Loss-of-function studies showed that SIRT6, a nuclear NAD⁺-dependent deacetylase, maintains disc health. We therefore investigated whether long-term SIRT6 activation via systemic delivery of the small-molecular agonist MDL-800 improves disc health in 24-month-old mice. Studies revealed healthy disc morphology, enhanced cell viability, and lower degeneration scores following MDL-800 treatment. SIRT6 activation decreased H3K9ac levels, improved extracellular matrix quality, and reduced senescence, as evidenced by lower levels of p21, IL-6, TGF-β, and CCL2. Tissue RNA-Seq, measurements of histone 3 modification, and multi-omics ATAC-seq/RNA-seq revealed altered epigenetic (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscapes. MDL-800 increased autophagy without affecting disc cellular bioenergetics. Plasma metabolomics, scRNA-sequencing of lymphoid tissues (bone marrow and spleen), and cytokine profiling showed good systemic tolerance of the treatment. While we noted a small decrease in vertebral structural parameters and mild hyperalgesia in treated cohorts, there were no vertebral fractures, and the broader motor function and behavior remained unaffected, raising no safety concerns. Our studies underscore the feasibility of SIRT6 activation as a pharmacological strategy to maintain the health of the aging spine.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70709"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222915","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":"Chronic Senolytic Treatment and/or Aerobic Exercise Reduce Senescence and Improve Myocardial Function During Aging in the Heart.","authors":"Ryan T Bevington, Amanda L Johnson, Briana L Hockey, Val A Fajardo, Gianni Parise","doi":"10.1111/acel.70759","DOIUrl":"10.1111/acel.70759","url":null,"abstract":"<p><p>Aging is the predominant risk factor for cardiac dysfunction, driven primarily through a decline in cardiomyocyte and overall myocardial performance. Cellular senescence is becoming increasingly linked to its development, as senescent cardiomyocytes and interstitial cells accumulate with age and exhibit persistent DNA damage, mitochondrial dysfunction, and inflammation that collectively impair ventricular relaxation and contractility. Senolytics, which selectively eliminate senescent cells, effectively clear cardiac senescence and its burden, while aerobic exercise has shown promise as a non-pharmacological intervention capable of modulating senescence. Despite this, neither approach has been evaluated as a long-term preventive strategy or whether combining exercise with senolytics produces an additive effect. We hypothesized that when combined, chronic senolytics and aerobic exercise would produce a synergistic clearance of senescent myocardial cells leading to improved cardiac function. Male and female C57BL/6N mice (12-months-old) were randomly allocated to each group and received their intervention for 9-months: naturally aged (VEH, n = 12), aerobic exercise (EX, n = 11), senolytics Dasatinib + Quercetin (D + Q) (SEN, n = 15) or both combined (SENEX, n = 16). Chronic D + Q, exercise, or both, significantly lowered the proportion of p16+, p21+, and γ-H2AX+ cardiomyocytes and interstitial cells, while improving myocardial performance and diastolic function compared to naturally aged mice. At the whole-heart level, protein expression of p16 and p21 increased with age, but was not altered alongside SASP by any intervention. Collectively, these findings demonstrate that long-term exercise or senolytics limit senescence at the cellular level within the myocardium, and improve ventricular function, positioning exercise or senolytics as promising strategies to mitigate age-related cardiac dysfunction.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70759"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126153","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":"METTL14-Mediated m⁶A Methylation Preserves Cardiomyocyte Homeostasis and Attenuates Progeria-Associated Cardiac Remodeling.","authors":"Shixiao Wang, Jie Zhang, Ying Ao, Dan Rao, Cong Yu, Chenzhong Xu, Ming Wang, Mingying Li, Xin Huang, Jianfei Zhang, Rui Mei, Zhen Zhang, Jie Sun, Juanli Duan, Ying Sun, Zimei Wang, Wen Su, Baohua Liu","doi":"10.1111/acel.70765","DOIUrl":"10.1111/acel.70765","url":null,"abstract":"<p><p>Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder most commonly caused by a de novo synonymous mutation (c.1824C>T) in the LMNA gene. This mutation activates aberrant splicing of prelamin A, leading to the production and accumulation of progerin, which drives accelerated aging, with patients predominantly succumbing to cardiovascular disease. However, while cardiac pathologies are well documented, the cell-autonomous contribution of cardiomyocytes to HGPS-associated cardiac remodeling remains poorly understood. Here, we generated a cardiomyocyte-specific progerin-expressing mouse model (Myh6-Cre; Lmna^fl/fl) and found that selective progerin expression in cardiomyocytes was sufficient to recapitulate key cardiac features of HGPS, including myocardial fibrosis, cardiac hypertrophy, and progressive functional decline. Mechanistically, progerin-expressing hearts exhibited a marked reduction in the N⁶-methyladenosine (m⁶A) writer components METTL3/14, and knockdown of Mettl3/14 in primary cardiomyocytes decreased the expression of calcium-handling transcript (Casq2), while elevating senescence-related (Cdkn1a and Cdkn2a) and pro-inflammatory transcripts (Ifna and Ifnb). Importantly, cardiomyocyte-targeted restoration of METTL14 partially ameliorated pathological cardiac remodeling and dysfunction in progeroid mice. Together, the data identify METTL14-dependent m⁶A methylation as a critical regulator of cardiomyocyte integrity during progeria-associated cardiac remodeling. Restoration of cardiac m⁶A writer activity may represent a potential therapeutic strategy for laminopathy-related cardiovascular aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70765"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190415","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}