{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:16:51Z","timestamp":1790252211785,"version":"4.1.0"},"reference-count":62,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T00:00:00Z","timestamp":1759622400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T00:00:00Z","timestamp":1759622400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100016374","name":"Cures Within Reach","doi-asserted-by":"publisher","award":["P30ES036084"],"award-info":[{"award-number":["P30ES036084"]}],"id":[{"id":"10.13039\/100016374","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["P30ES020957"],"award-info":[{"award-number":["P30ES020957"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R01ES033171"],"award-info":[{"award-number":["R01ES033171"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["RF1AG078170"],"award-info":[{"award-number":["RF1AG078170"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30ES036084"],"award-info":[{"award-number":["P30ES036084"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA022453"],"award-info":[{"award-number":["P30CA022453"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD030484"],"award-info":[{"award-number":["S10OD030484"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA\u2010approved sodium\u2010glucose co\u2010transporter 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\u2010omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM\u2010HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP\u2013PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal\u2010dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite\u2010level 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\u2010specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex\u2010specific mechanisms.<\/jats:p>","DOI":"10.1111\/acel.70255","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T06:41:31Z","timestamp":1759732891000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Canagliflozin Reprograms the Aging Hippocampus in Genetically Diverse\n                    <scp>UM<\/scp>\n                    \u2010\n                    <scp>HET<\/scp>\n                    3 Mice and Attenuates Alzheimer's\u2010Like Pathology"],"prefix":"10.1111","volume":"24","author":[{"given":"Hashan","family":"Jayarathne","sequence":"first","affiliation":[{"name":"Department of Biological Sciences Wayne State University  Detroit Michigan 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 Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Wayne State University  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Chimienti","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Wayne State University  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Kadri","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Wayne State University  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Gurdziel","sequence":"additional","affiliation":[{"name":"Institute of Environmental Health Sciences, Integrative Biosciences Center Wayne State University  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seongho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine, Karmanos Cancer Institute Wayne State University  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyejeong","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine, Karmanos Cancer Institute Wayne State University  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett C.","family":"Ginsburg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences University of Texas Health Science Center  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Pathology and Geriatrics Center University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoshana","family":"Yakar","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, David B. Kriser Dental Center New York University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Sadagurski","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Wayne State University  Detroit Michigan USA"},{"name":"Institute of Environmental Health Sciences, Integrative Biosciences Center Wayne State University  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu11092161"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567205011310020003"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2016.09.004"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.03.007"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22745"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2006.045716"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S86958"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2175569"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/01635581.2020.1804949"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.1065904"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2165\/11597760-000000000-00000"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2006-10113"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10051093"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00089"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glab216"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.87340.3"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(99)00060-X"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.967747"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12656"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.06.002"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90312-E"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/biof.1166"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12898"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12170"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-017-0245-y"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/neurolint16060124"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-024-01214-z"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13653"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-024-01198-w"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9382-9"},{"key":"e_1_2_9_32_1","volume-title":"Mediating the Metabolic and Antiproliferative Effects of Biguanidesed","author":"Lefran\u00e7ois G.","year":"2024"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e28808"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.964429"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-006-9170-3"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.140019"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13065-019-0597-4"},{"key":"e_1_2_9_38_1","first-page":"609","article-title":"Glutathione Metabolism Enzymes in Brain and Liver of Hyperphenylalaninemic Rats and the Effect of Lipoic Acid Treatment","volume":"29","author":"Moraes T. B.","year":"2014","journal-title":"Metabolic Brain Disease"},{"key":"e_1_2_9_39_1","doi-asserted-by":"crossref","first-page":"856","DOI":"10.31083\/ph.2014.4647","article-title":"Gender Differences in the Gene Expression Profiles of Glucose Transporter GLUT Class I and SGLT in Mouse Tissues","volume":"69","author":"Nagai K.","year":"2014","journal-title":"Die Pharmazie"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.713726"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1159\/000543533"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04543"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.102328"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33735-6"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-014-0225-5"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0864-09.2009"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2014.00742"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-024-02502-y"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.308395"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2025.0360"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-210523"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-022-00641-0"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr597"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjdrc-2020-001765"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1142179"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03605-4"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.800490"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.18.6243-6253.2001"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.101261"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glz135"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756285612461679"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32590-X"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70255","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70255","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70255","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T03:26:24Z","timestamp":1780457184000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,5]]},"references-count":62,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1111\/acel.70255"],"URL":"https:\/\/doi.org\/10.1111\/acel.70255","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,5]]},"assertion":[{"value":"2025-06-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70255"}}