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The purpose of this study was to identify changes in whole blood transcriptome from a course of metformin in a randomized trial (NCT02684578) of nondiabetic older adults with age-related macular degeneration (AMD). We included patients who were\u2009\u2265\u200955\u00a0years of age, nondiabetic, and had geographic atrophy due to AMD. We excluded patients with metformin use for another reason, reduced renal or liver function, or other vitreoretinal diseases. Participants were randomized to metformin or control. The metformin group was prescribed 1000\u00a0mg metformin twice daily for 18\u00a0months. All eligible patients were approached for consent to blood sample collection. We performed metagenomic sequencing on whole blood samples and conducted differential expression analysis. Fifteen patients underwent blood collection, with eight in the metformin group and seven in the control group. No individual gene achieved statistical significance of difference between groups after correction for multiple comparisons. As a secondary, hypothesis-generating analysis, canonical pathway analysis found downregulation of interferon \u03b1\/\u03b2 signaling (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.003, z score\u2009=\u2009\u22122.4), cell junction organization (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.03, z score\u2009=\u2009\u22122.2), and epithelial mesenchymal transition pathways in the metformin group (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.02, z score\u2009=\u2009\u22122.2). There was possible inhibition of upstream proinflammatory molecules and activation of anti-inflammatory molecules by metformin. In this small sub-study of a randomized trial, no gene was significantly changed after metformin exposure. Pathway enrichment analysis identified signals potentially consistent with metformin-associated modulation of \u201cinflammaging\u201d and other biological pathways which require validation in larger cohorts.\n                  <\/jats:p>","DOI":"10.1007\/s11357-026-02593-1","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:49:35Z","timestamp":1792504175000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An exploratory study of the effect of metformin on the whole blood transcriptome of nondiabetic older adults with age-related macular degeneration"],"prefix":"10.1007","author":[{"given":"Xinyi","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi S.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisy","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuy","family":"Doan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangbo L.","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abu T.","family":"Taha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Psaras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn K.","family":"Callander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole Y.","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun","family":"Shivkumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amani A.","family":"Fawzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn","family":"Yiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Telander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loh-Shan B.","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Flaxel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Newman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy D.","family":"Keenan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1054-3423","authenticated-orcid":false,"given":"Jay M.","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"2593_CR1","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.1038\/ncomms3192","volume":"4","author":"A Martin-Montalvo","year":"2013","unstructured":"Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. 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Chen, None; Y.S. Zhang, None; D. Yan, None; T. Doan, None; L.L. Shen, Boehringer-Ingelheim (C); A.T. Taha, None; D. Yang, None; C. Psaras, None; J.K. Callander, None; N. Xin, None; A. Shivkumar, None; A.A. Fawzi, Roche\/Genentech (C), Boehringer Ingelheim (C), RegenXbio (C), 3Helix (C); G. Yiu, 4DMT (C), Abbvie (C), Adverum (C), Alcon (C), Bausch & Lomb (C), Boehringer Ingelheim (C), Clearside Biomedical (C), Coave (C), Genentech (C), jCyte (C), Merck (C), Mobius (C), Nanoscope (C), Ocuphire (C), Opthea (C), Osanni (C), Ray BioTherapeutics (C), RegenXBio (C), Roche (C), Samsung Bioepis (C), Stealth Therapeutics (C), SunRegen (C), Supra Medical (C), Surrozen (C), West Pharmaceutical (C); D.G. Telander, None; L.B. Leung, None; C. Flaxel, None; J.C. Newman, co-founder, holds equity, and is inventor on patents licensed to Component Health, Selah Therapeutics, and BOPZ, also on the scientific advisory board of Junevity Inc.; J.D. Keenan, None; J.M. Stewart, Carl Zeiss (C), Merck (C), Valitor (C, I), Long Bridge (C, I), Twenty Twenty (C), Oculgen (C), Science (C, I), Boehringer-Ingelheim (C), ANI (C), Spraktical (C, I).","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}