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In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because males show decreased expression of select X factors (XY). While each sex (XX and XY) harbors one active X due to X chromosome inactivation in females, some genes, such as Kdm6a, transcriptionally escape silencing in females\u2014resulting in lower transcript levels in males. Kdm6a is a known histone demethylase (H3K27me2\/3) with multiple functional domains that is linked with synaptic plasticity and cognition. Whether elevating Kdm6a could benefit the aged male brain and whether this requires its demethylase function remains unknown. We used lentiviral-mediated overexpression of the X factor in the hippocampus of aging male mice and tested their cognition and behavior in the Morris water-maze. We found that acutely increasing Kdm6a\u2014in a form without demethylase function\u2014selectively improved learning and memory, in the aging XY brain, without altering total activity or anxiety-like measures. Further understanding the demethylase-independent downstream mechanisms of Kdm6a may lead to novel therapies for treating age-induced cognitive deficits in both sexes.<\/jats:p>","DOI":"10.1093\/gerona\/glad007","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T02:28:36Z","timestamp":1673231316000},"page":"938-943","source":"Crossref","is-referenced-by-count":31,"title":["X Chromosome Factor Kdm6a Enhances Cognition Independent of Its Demethylase Function in the Aging XY Male\u00a0Brain"],"prefix":"10.1093","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6636-9810","authenticated-orcid":false,"given":"Cayce\u00a0K","family":"Shaw","sequence":"first","affiliation":[{"name":"Department of Neurology and Weill Institute for Neurosciences, University of California , San Francisco, California , USA"},{"name":"Rehabilitation Sciences Graduate Program, University of California , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira","family":"Abdulai-Saiku","sequence":"additional","affiliation":[{"name":"Department of Neurology and Weill Institute for Neurosciences, University of California , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Marino","sequence":"additional","affiliation":[{"name":"Department of Neurology and Weill Institute for Neurosciences, University of California , San Francisco, California , USA"},{"name":"Neuroscience Graduate Program, University of California , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Weill Institute for Neurosciences, University of California , San Francisco, California , 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