{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:52:38Z","timestamp":1791309158060,"version":"4.3.1"},"posted":{"date-parts":[[2026,10,1]]},"group-title":"Neuroscience","reference-count":154,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Longevity Consortium","award":["U19 AG023122"],"award-info":[{"award-number":["U19 AG023122"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>Aging is the strongest risk factor for Alzheimer\u2019s disease (AD), yet existing human neuronal models either erase age-associated features during reprogramming or fail to recapitulate three-dimensional organization of human neuronal tissue. Here, we establish directly induced neuronal spheroids (iSpheroids), a scalable three-dimensional platform generated by direct conversion of primary fibroblasts without pluripotency. iSpheroids generate long-lived, electrophysiologically active neurons from young, unimpaired aged, and sporadic AD donors while preserving donor-specific epigenetic age. Single-nucleus RNA sequencing revealed approximately 96% of cells acquired a neuronal identity and were distributed across multiple neuronal states, including a diversity of neurons. The platform supports incorporation of astrocytes and microglia and generation from non-human primate fibroblasts. AD iSpheroids spontaneously recapitulated neuronal degeneration, amyloid-\u03b2 accumulation, progressive Tau pathology, and metabolic dysfunction. Integrated proteomic, metabolomic, and lipidomic profiling distinguished physiological aging from AD and revealed disease-associated metabolic remodeling. Oxaliplatin shifted AD iSpheroids toward oxidative metabolism, whereas a multi-compound screen identified trametinib as a modulator of inflammatory and age-associated programs.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"755853v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"simple\">\n                    <jats:list-item>\n                      <jats:p>- Direct conversion generates age-preserving, functional human neuronal iSpheroids.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>- iSpheroids recapitulate molecular and pathological hallmarks of AD.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>- Multi-omics distinguishes physiological neuronal aging from AD.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>- Pharmacological screening identifies reversible metabolic and inflammatory phenotypes.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.30.755853","type":"posted-content","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:10:18Z","timestamp":1790871018000},"source":"Crossref","is-referenced-by-count":0,"title":["An age-preserving neuronal iSpheroid platform for modeling human aging and Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Samhan","family":"Alsolami","sequence":"first","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"},{"name":"University of California, Los Angeles, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais Sarraf","family":"Sabedot","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Upendra","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology (BMB), Sealy Institute for Drug Discovery (SIDD), University of Texas Medical Branch (UTMB), Galveston, TX, 77555-1068, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Kirk","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Skvir","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chynna","family":"Bowman","sequence":"additional","affiliation":[{"name":"Waitt Advanced Biophotonics Core, The Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Oiwa","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjan","family":"Mahmoudi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Cuoco","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Cranston","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Lucciola","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Boassa","sequence":"additional","affiliation":[{"name":"Waitt Advanced Biophotonics Core, The Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Herdy","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Jones","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"},{"name":"Department of Neuroscience, University of Florida, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuori","family":"Yoshikiyo","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Longevity Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Mertens","sequence":"additional","affiliation":[{"name":"Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Martinez-Trujillo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz","family":"Jaremko","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology (BMB), Sealy Institute for Drug Discovery (SIDD), University of Texas Medical Branch (UTMB), Galveston, TX, 77555-1068, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George 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