{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T12:19:19Z","timestamp":1783685959148,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Frailty is a multidimensional geriatric syndrome that lacks a consistent definition, complicating its clinical management. Epigenetic data suggest that frailty involves altered CpG sites, potentially driven by environmental epigenetic factors (the exposome) that influence aging. Systematically reviewing studies from 2009 to 2025, we quantified frailty prevalence, pooled weighted methylation beta values for associated CpG sites, performed enrichment analysis, and conducted structural network analysis to evaluate chemical interactions, following the PRISMA 2020 guidelines and with the study prospectively registered in PROSPERO (ID 1159037). Results showed a pooled frailty prevalence of 17.4% with extreme heterogeneity (I2 = 98.88%), and a combined methylated beta effect of \u22120.1378 (CI: \u22120.4156, 0.1400) with high heterogeneity (I2 = 100%), highlighting sources of variability. Interestingly, we found a CpG site (cg04772644) shared between Chinese and German cohorts, and, upon mapping, four frailty-related genes (CDC42BPB, SLC1A5, RXRB, and SLC22A18AS) were shared across cohorts. Indeed, these genes are significantly enriched in pathways including thrombin signaling, G protein-coupled receptor signaling, and immune cell differentiation signaling. Finally, our system toxicology analysis demonstrated that arsenite, bisphenol A, benzamide, dorsomorphin, and trichostatin A directly interact with the four shared genes, suggesting that the chemical exposome contributes to the observed epigenetic heterogeneity of frailty and the concomitant clinical manifestations.<\/jats:p>","DOI":"10.3390\/ijms27135986","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T14:33:06Z","timestamp":1783089186000},"page":"5986","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Signatures of Frailty: A Systematic Review, Meta-Analysis, and Network Analysis of the Chemical Exposome"],"prefix":"10.3390","volume":"27","author":[{"given":"Alejandro Eliu","family":"Cedillo-Rivero","sequence":"first","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Instituto Nacional de Geriatr\u00eda, Mexico City 10200, Mexico"},{"name":"Secretar\u00eda de Ciencias, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n (SECIHTI, Formerly CONAHCYT), Programa de Doctorado en Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian Daniel","family":"Rodriguez-Cuartas","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Instituto Nacional de Geriatr\u00eda, Mexico City 10200, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Gomez-Zapata","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Instituto Nacional de Geriatr\u00eda, Mexico City 10200, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2649-8751","authenticated-orcid":false,"given":"Edgar","family":"Flores-Soto","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de Mexico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7186-8067","authenticated-orcid":false,"given":"Juan Carlos","family":"Gomez-Verjan","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Instituto Nacional de Geriatr\u00eda, Mexico City 10200, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2659-6864","authenticated-orcid":false,"given":"Nadia Alejandra","family":"Rivero-Segura","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Instituto Nacional de Geriatr\u00eda, Mexico City 10200, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1080\/21505594.2016.1219445","article-title":"Geriatric Syndromes: How to Treat","volume":"8","author":"Cesari","year":"2017","journal-title":"Virulence"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dong, Y., and Hu, Q. 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