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In pregnancies affected by complications such as pre\u2010eclampsia and fetal growth restriction, placental ageing is notably accelerated and observed at an earlier gestational age. Metformin is used during pregnancy for an increasing variety of indications, including treatment of gestational diabetes, and may have a role in slowing cellular ageing. It is therefore essential to understand the potential impact of metformin on placental ageing. Placental samples (<jats:italic>n<\/jats:italic>\u00a0=\u00a0105) were obtained from women with body mass index \u226530\u00a0kg\/m<jats:sup>2<\/jats:sup> and who were randomized to treatment with metformin or placebo during pregnancy. Ageing was assessed by measuring telomere length, histological examination, and using array\u2010based technologies to investigate gene expression and methylation. Results were validated using isolated human trophoblasts treated <jats:italic>in vitro<\/jats:italic> with metformin, and in a complementary mouse model. There were no differences between metformin\u2010exposed and control placentas in terms of telomere length, fibrosis or calcification. There were no differences in placental gene expression or methylation patterns by metformin status. In our mouse model, no genes classically associated with cellular ageing were differentially expressed and no senescence pathway showed evidence of enrichment with metformin treatment. There was no evidence that metformin either slows or accelerates placental ageing pathways in the complementary models that we investigated. Our findings are reassuring with regard to the safety of metformin used to treat gestational diabetes, but do not support a role for metformin in the prevention of adverse pregnancy outcomes in non\u2010diabetic women.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16782-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Accelerated placental ageing, where the senescent phenotype that normally accumulates over a healthy pregnancy is observed at a premature gestational age, is associated with adverse pregnancy outcomes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Metformin has been proposed as an anti\u2010ageing drug elsewhere. Therefore, metformin could alter the trajectory of placental ageing and prevent associated pregnancy complications.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The present study incorporated human data from a randomized clinical trial and complementary models. Metformin did not impact methylation\u2010predicted gestational age, telomere length, gene expression or histological ageing in human placentas treated <jats:italic>in vivo<\/jats:italic>, isolated trophoblasts treated <jats:italic>in vitro<\/jats:italic> or mouse models.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Metformin neither decelerated nor accelerated placental ageing, thereby supporting its continued use in the obstetric setting, for instance in the treatment of gestational diabetes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Metformin cannot be recommended to prevent adverse pregnancy outcomes because we found no evidence suggesting it decelerates placental ageing. Further research is warranted to find drug therapies for this purpose.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp288710","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T14:45:08Z","timestamp":1748702708000},"page":"3463-3477","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The impact of metformin on placental ageing in humans and mice"],"prefix":"10.1113","volume":"603","author":[{"given":"Grace J.","family":"Hattersley","sequence":"first","affiliation":[{"name":"University of Cambridge School of Clinical Medicine  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Yang","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, Queen's Medical Research Institute University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane L.","family":"Tarry\u2010Adkins","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, the Rosie Hospital and NIHR Cambridge Biomedical Research Centre University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Hufnagel","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Science \u2013 Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Addenbrooke's Hospital University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6378-3434","authenticated-orcid":false,"given":"Kwun Kiu","family":"Wong","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Science \u2013 Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Addenbrooke's Hospital University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise S.","family":"Fernandez\u2010Twinn","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Science \u2013 Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Addenbrooke's Hospital University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Chukanova","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, the Rosie Hospital and NIHR Cambridge Biomedical Research Centre University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"India G.","family":"Robinson","sequence":"additional","affiliation":[{"name":"University of Cambridge School of Clinical Medicine  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Drake","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, Queen's Medical Research Institute University of Edinburgh  Edinburgh 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Research Laboratories and MRC Metabolic Diseases Unit, Addenbrooke's Hospital University of Cambridge  Cambridge UK"},{"name":"Loke Centre for Trophoblast Research University of Cambridge  Cambridge 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