{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T20:38:16Z","timestamp":1790455096029,"version":"4.1.0"},"reference-count":305,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"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>Metformin, an oral antihyperglycemic drug, represents the cornerstone of pharmacological treatment for type 2 diabetes mellitus (T2DM). Its primary glucose-lowering effects are well established, predominantly mediated through the activation of AMP-activated protein kinase (AMPK). This activation leads to a reduction in hepatic glucose production (primarily by inhibiting gluconeogenesis and glycogenolysis) and an increase in peripheral glucose uptake and utilization. Beyond its direct impact on glucose metabolism, metformin also improves insulin sensitivity and has beneficial effects on lipid profiles. Increasingly, research shows that metformin has pleiotropic effects. In addition to its recognized antihyperglycemic action, metformin is emerging as a regulator of cellular processes implicated in aging. Indeed, emerging evidence suggests a potential role of metformin in modulating pathways associated with longevity and ameliorating the symptoms of age-related diseases, including neurodegenerative disorders (such as Alzheimer\u2019s and Parkinson\u2019s diseases), cardiovascular diseases, age-related macular degeneration, and osteoporosis. The proposed mechanisms for these broader effects involve AMPK activation, modulation of the mTOR pathway, reduction of oxidative stress, and promotion of autophagy. After exploring the established role of metformin in T2D, this review provides a comprehensive investigation of its promising applications in the context of age-related diseases, offering valuable insights into its multifaceted therapeutic potential beyond glycemic control.<\/jats:p>","DOI":"10.3390\/ijms26199748","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T10:48:07Z","timestamp":1759834087000},"page":"9748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6680-216X","authenticated-orcid":false,"given":"Lucrezia Irene Maria","family":"Campagnoli","sequence":"first","affiliation":[{"name":"Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Varesi","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada"},{"name":"Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Foroogh","family":"Fahmideh","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Hakimizad","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Petkovic","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2947-0084","authenticated-orcid":false,"given":"Annalisa","family":"Barbieri","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-1420","authenticated-orcid":false,"given":"Nicoletta","family":"Marchesi","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7182-4272","authenticated-orcid":false,"given":"Alessia","family":"Pascale","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","article-title":"Metformin: Historical Overview","volume":"60","author":"Bailey","year":"2017","journal-title":"Diabetologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1210\/endrev\/bnaa023","article-title":"Cellular and Molecular Mechanisms of Metformin Action","volume":"42","author":"LaMoia","year":"2021","journal-title":"Endocr. 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