{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T02:50:02Z","timestamp":1784688602706,"version":"3.55.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Cardiac aging is a major risk factor for the development of cardiovascular diseases. Although evidence suggests an association between N6-methyladenosine (m6A) modification and numerous cardiovascular diseases, its role in cardiac aging remains unclear. This study was conducted to elucidate the role of m6A modification in cardiac aging and the molecular mechanisms involved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Global methylation levels and the expression of major m6A regulators were compared between young and aged hearts. Transcriptome-wide m6A landscape analysis was conducted using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) to identify aberrant m6A peaks. Furthermore, gene set enrichment analysis (GSEA) was performed to identify gene sets associated with cardiac aging. Functional validation of key molecules was carried out through <jats:italic>in vitro<\/jats:italic> experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The overall m6A level remained constant; however, the expression of the methyltransferase METTL14 and the demethyltransferase FTO were significantly upregulated in aged hearts. Knockdown of METTL14 alleviated H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-induced senescence phenotypes, as reflected by a reduction in the number of SA-\u03b2-gal positive cells and a decrease in p21 expression. Compared with young hearts, the dysregulated m6A peaks were significantly enriched in genes associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, and the PI3K-Akt signaling pathway. GSEA showed that these genes were enriched in the aging of heart and aorta cardiomyocytes. Additionally, 255 genes with siginificantly changed of both m6A peaks and RNA expression were identified by combining MeRIP-seq and RNA-seq data. Among these genes, EFEMP1 was significantly upregulated in aged hearts, accompanied by enhanced m6A modification. Treatment with the methyltransferase inhibitor cycloleucine significantly suppressed the expression level of EFEMP1. In AC16 cells, silencing EFEMP1 suppressed H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-induced cell senescence. Furthermore, we found a positive correlation between METTL14 and EFEMP1 in multiple datasets related to cardiac aging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that m6A modification plays an essential role in the process of cardiac aging. EFEMP1 may serve as a potential new therapeutic target for age-related cardiac diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2025.1563364","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T05:49:10Z","timestamp":1750225750000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["N6-methyladenosine RNA landscape in the aged mouse hearts"],"prefix":"10.3389","volume":"12","author":[{"given":"Xia","family":"Jing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaofu","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Yu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Yang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Peng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Liang","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinguang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuguo","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Dong","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"eabg7073","DOI":"10.1126\/sciadv.abg7073","article-title":"Regulation of telomere homeostasis and genomic stability in cancer by N(6)-adenosine methylation (m(6)A)","volume":"7","author":"Lee","year":"2021","journal-title":"Sci Adv"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global burden of cardiovascular diseases and risk factors, 1990\u20132019: update from the GBD 2019 study","volume":"76","author":"Roth","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1161\/CIRCRESAHA.119.315889","article-title":"Targeting age-related pathways in heart failure","volume":"126","author":"Li","year":"2020","journal-title":"Circ Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"C166","DOI":"10.1152\/ajpcell.00021.2020","article-title":"Cardiac tissue remodeling in healthy aging: the road to pathology","volume":"319","author":"Tracy","year":"2020","journal-title":"Am J Physiol Cell Physiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/nrg3724","article-title":"Gene expression regulation mediated through reversible m(6)A RNA methylation","volume":"15","author":"Fu","year":"2014","journal-title":"Nat Rev Genet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"149113","DOI":"10.1016\/j.bbrc.2023.10.045","article-title":"IGF2BP1 enhances the stability of SIK2 mRNA through m(6)A modification to promote non-small cell lung cancer progression","volume":"684","author":"Xu","year":"2023","journal-title":"Biochem Biophys Res Commun"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e1405","DOI":"10.1002\/ctm2.1405","article-title":"METTL3-mediated M(6) A modification of circPRKAR1B promotes Crohn\u2019s colitis by inducing pyroptosis via autophagy inhibition","volume":"13","author":"Zhao","year":"2023","journal-title":"Clin Transl Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"eadf3292","DOI":"10.1126\/sciadv.adf3292","article-title":"m(6)A RNA demethylase AtALKBH9B promotes mobilization of a heat-activated long terminal repeat retrotransposon in Arabidopsis","volume":"9","author":"Fan","year":"2023","journal-title":"Sci Adv"},{"key":"B9","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1161\/CIRCULATIONAHA.118.036146","article-title":"The N(6)-methyladenosine mRNA methylase METTL3 controls cardiac homeostasis and hypertrophy","volume":"139","author":"Dorn","year":"2019","journal-title":"Circulation"},{"key":"B10","doi-asserted-by":"publisher","first-page":"268","DOI":"10.7150\/thno.47021","article-title":"Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction","volume":"11","author":"Liao","year":"2021","journal-title":"Theranostics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1093\/cvr\/cvab161","article-title":"Senescence mechanisms and targets in the heart","volume":"118","author":"Chen","year":"2022","journal-title":"Cardiovasc Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.freeradbiomed.2014.03.018","article-title":"Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function","volume":"71","author":"Zhang","year":"2014","journal-title":"Free Radic Biol Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1161\/CIRCRESAHA.115.307778","article-title":"Revisiting cardiac cellular composition","volume":"118","author":"Pinto","year":"2016","journal-title":"Circ Res"},{"key":"B14","doi-asserted-by":"publisher","first-page":"gkae1176","DOI":"10.1093\/nar\/gkae1176","article-title":"Downregulation of MLF1 safeguards cardiomyocytes against senescence-associated chromatin opening","volume":"53","author":"Lv","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1016\/j.ymthe.2020.08.010","article-title":"M(6)A RNA methylation in cardiovascular diseases","volume":"28","author":"Wu","year":"2020","journal-title":"Mol Ther"},{"key":"B16","doi-asserted-by":"publisher","first-page":"6762","DOI":"10.1038\/s41467-022-34434-y","article-title":"METTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury","volume":"13","author":"Wang","year":"2022","journal-title":"Nat Commun"},{"key":"B17","doi-asserted-by":"publisher","first-page":"654316","DOI":"10.3389\/fphar.2021.654316","article-title":"Aging-associated differences in epitranscriptomic m6A regulation in response to acute cardiac ischemia\/reperfusion injury in female mice","volume":"12","author":"Su","year":"2021","journal-title":"Front Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"762853","DOI":"10.3389\/fcell.2021.762853","article-title":"Mettl14 attenuates cardiac ischemia\/reperfusion injury by regulating Wnt1\/beta-catenin signaling pathway","volume":"9","author":"Pang","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"8939","DOI":"10.7150\/thno.45178","article-title":"METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications","volume":"10","author":"Jian","year":"2020","journal-title":"Theranostics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1167132","DOI":"10.3389\/fcvm.2023.1167132","article-title":"Levels and clinical significance of the m6A methyltransferase METTL14 in patients with coronary heart disease","volume":"10","author":"Guo","year":"2023","journal-title":"Front Cardiovasc Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"101050","DOI":"10.1016\/j.gendis.2023.06.019","article-title":"Increased N6-methyladenosine is related to the promotion of the methyltransferase METTL14 in ovarian aging","volume":"11","author":"Qian","year":"2024","journal-title":"Genes Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1161\/CIRCULATIONAHA.118.033794","article-title":"FTO-dependent N(6)-methyladenosine regulates cardiac function during remodeling and repair","volume":"139","author":"Mathiyalagan","year":"2019","journal-title":"Circulation"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5443","DOI":"10.1080\/21655979.2022.2030572","article-title":"M(6)A demethylase FTO regulates the apoptosis and inflammation of cardiomyocytes via YAP1 in ischemia-reperfusion injury","volume":"13","author":"Ke","year":"2022","journal-title":"Bioengineered"},{"key":"B24","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1136\/jmedgenet-2015-103399","article-title":"Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay","volume":"53","author":"Daoud","year":"2016","journal-title":"J Med Genet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nrm.2016.132","article-title":"Post-transcriptional gene regulation by mRNA modifications","volume":"18","author":"Zhao","year":"2017","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3417","DOI":"10.1021\/acs.accounts.3c00448","article-title":"Emerging roles of RNA methylation in development","volume":"56","author":"Wang","year":"2023","journal-title":"Acc Chem Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"4710","DOI":"10.7150\/thno.51739","article-title":"Deficiency of telomere-associated repressor activator protein 1 precipitates cardiac aging in mice via p53\/PPARalpha signaling","volume":"11","author":"Cai","year":"2021","journal-title":"Theranostics"},{"key":"B28","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.bbrc.2017.03.053","article-title":"Nuclear AMPK regulated CARM1 stabilization impacts autophagy in aged heart","volume":"486","author":"Li","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"B29","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.tem.2015.05.010","article-title":"AMPK: energy sensor and survival mechanism in the ischemic heart","volume":"26","author":"Qi","year":"2015","journal-title":"Trends Endocrinol Metab"},{"key":"B30","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1161\/CIRCULATIONAHA.110.953208","article-title":"Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart","volume":"122","author":"Ma","year":"2010","journal-title":"Circulation"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1093\/eurheartj\/ehq253","article-title":"Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia\/reperfusion injury: role of autophagy paradox and toxic aldehyde","volume":"32","author":"Ma","year":"2011","journal-title":"Eur Heart J"},{"key":"B32","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1111\/1440-1681.12791","article-title":"Dexmedetomidine protects mice against myocardium ischaemic\/reperfusion injury by activating an AMPK\/PI3K\/Akt\/eNOS pathway","volume":"44","author":"Sun","year":"2017","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"549","DOI":"10.3892\/mmr.2019.10864","article-title":"Swimming exercise inhibits myocardial ER stress in the hearts of aged mice by enhancing cGMP-PKG signaling","volume":"21","author":"Chang","year":"2019","journal-title":"Mol Med Rep"},{"key":"B34","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1038\/s41576-018-0004-3","article-title":"DNA methylation-based biomarkers and the epigenetic clock theory of ageing","volume":"19","author":"Horvath","year":"2018","journal-title":"Nat Rev Genet"},{"key":"B35","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1038\/s41392-022-01211-8","article-title":"Epigenetic regulation of aging: implications for interventions of aging and diseases","volume":"7","author":"Wang","year":"2022","journal-title":"Signal Transduct Target Ther"},{"key":"B36","doi-asserted-by":"publisher","first-page":"103056","DOI":"10.1016\/j.cpcardiol.2025.103056","article-title":"Histone modifications as molecular drivers of cardiac aging: metabolic alterations, epigenetic mechanisms, and emerging therapeutic strategies","volume":"50","author":"Alrumaihi","year":"2025","journal-title":"Curr Probl Cardiol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1172\/JCI83083","article-title":"Endothelial fluid shear stress sensing in vascular health and disease","volume":"126","author":"Baeyens","year":"2016","journal-title":"J Clin Invest"},{"key":"B38","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1093\/cvr\/cvp035","article-title":"Cardioprotection by hypoxia-inducible factor 1 alpha transfection in skeletal muscle is dependent on haem oxygenase activity in mice","volume":"82","author":"Czibik","year":"2009","journal-title":"Cardiovasc Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1038\/s41374-022-00819-2","article-title":"Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db\/db mice","volume":"102","author":"Deng","year":"2022","journal-title":"Lab Invest"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e70515","DOI":"10.1096\/fj.202403086RR","article-title":"Proteomic analysis of liver fibrosis reveals EFEMP1 as a new modulator of focal adhesion and migration of hepatic stellate cells","volume":"39","author":"Thomas","year":"2025","journal-title":"FASEB J"},{"key":"B41","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1093\/cvr\/cvaf021","article-title":"Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition","volume":"121","author":"Timmer","year":"2025","journal-title":"Cardiovasc Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.3233\/JAD-215053","article-title":"Plasma EFEMP1 is associated with brain aging and dementia: the framingham heart study","volume":"85","author":"McGrath","year":"2022","journal-title":"J Alzheimers Dis"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2025.1563364\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T05:49:13Z","timestamp":1750225753000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2025.1563364\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":42,"alternative-id":["10.3389\/fcvm.2025.1563364"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2025.1563364","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]},"article-number":"1563364"}}