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The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP\u2013PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana\u2019s potential to combat brain aging and AD through sex-specific mechanisms.<\/jats:p>","DOI":"10.1101\/2025.06.10.658747","type":"posted-content","created":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T23:35:19Z","timestamp":1750030519000},"source":"Crossref","is-referenced-by-count":1,"title":["Canagliflozin reprograms the aging hippocampus in genetically diverse UM-HET3 mice and attenuates Alzheimer\u2019s-like pathology"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5213-3011","authenticated-orcid":false,"given":"Hashan","family":"Jayarathne","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Wayne State University, Detroit, MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4712-3576","authenticated-orcid":false,"given":"Dulmalika Herath","family":"Manchanayake","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Wayne State University, Detroit, MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Chimienti","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Wayne State University, Detroit, MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Kadri","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Wayne State University, Detroit, MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3784-072X","authenticated-orcid":false,"given":"Katherine","family":"Gurdziel","sequence":"additional","affiliation":[{"name":"Institute of Environmental Health Sciences, Integrative Biosciences Center, Wayne State University, Detroit, MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1120-073X","authenticated-orcid":false,"given":"Seongho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4502-6215","authenticated-orcid":false,"given":"Hyejeong","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4646-8744","authenticated-orcid":false,"given":"Brett C.","family":"Ginsburg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, San Antonio, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5252-505X","authenticated-orcid":false,"given":"Richard A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2352-1330","authenticated-orcid":false,"given":"Shoshana","family":"Yakar","sequence":"additional","affiliation":[{"name":"David B. 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