{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:07:46Z","timestamp":1789672066799,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,14]]},"group-title":"Genomics","reference-count":97,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH\/NIA","award":["R21 AG070527"],"award-info":[{"award-number":["R21 AG070527"]}]},{"name":"NIH\/NIA","award":["F99\/K00 AG083292"],"award-info":[{"award-number":["F99\/K00 AG083292"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Sex differences contribute to brain aging, neurodegenerative diseases, and more broadly in determining rates of aging across species. The hypothalamus plays a central role in physiological homeostasis and healthy aging, yet how its cellular and molecular landscape diverges between males and females over the lifespan remains poorly understood. Here, we present a single-nucleus multi-omics analysis of the hypothalamus in young, middle aged, and aged male and female mice. We identified major hypothalamic cell types and characterized their sex- and age-dependent transcriptional and chromatin accessibility profiles. Notably, female-specific changes on the X chromosome (chrX) emerged as a prominent feature of aging, including changes to the X inactivation center and an overall increase in chrX gene expression and accessibility in immune cells and neurons. Pseudotime analysis of immune cells revealed an aging trajectory with sex-specific multi-omic programs, featuring increased inflammation in females compared to males. Delving deeper into the epigenetic signatures associated with these sex differences, we found that H3K27me3 \u2013 the repressive histone mark enriched on the inactive X in females \u2013 increased in abundance and underwent substantial genome-wide redistribution with age in both sexes, particularly on the inactive chrX in females. Collectively, these findings highlight distinct cell-type-specific aging trajectories in the male and female hypothalamus, identify female aging signatures associated with X-linked epigenetic regulatory programs, and provide a comprehensive resource for understanding the molecular basis of sex differences in brain aging.<\/jats:p>","DOI":"10.64898\/2026.09.08.750001","type":"posted-content","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T17:20:53Z","timestamp":1789406453000},"source":"Crossref","is-referenced-by-count":0,"title":["Single-cell transcriptomic and epigenomic analysis reveals X-linked sex differences in aging mouse hypothalamus"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5142-0406","authenticated-orcid":false,"given":"Doudou","family":"Yu","sequence":"first","affiliation":[{"name":"Molecular Biology, Cell Biology, and Biochemistry Graduate Program, Brown University, Providence, RI, USA"},{"name":"The Buck Institute for Research on Aging, Novato, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya","family":"Osipov","sequence":"additional","affiliation":[{"name":"The Buck Institute for Research on Aging, Novato, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lexi-Amber","family":"Hassell","sequence":"additional","affiliation":[{"name":"Neuroscience Graduate Program, Brown University, Providence, RI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neta A.","family":"Shwartz","sequence":"additional","affiliation":[{"name":"The Buck Institute for Research on Aging, Novato, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn H.","family":"Hajdarovic","sequence":"additional","affiliation":[{"name":"Neuroscience Graduate Program, Brown University, Providence, RI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold","family":"Marin","sequence":"additional","affiliation":[{"name":"The Buck Institute for Research on Aging, Novato, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0441-2307","authenticated-orcid":false,"given":"Ashley E.","family":"Webb","sequence":"additional","affiliation":[{"name":"The Buck Institute for Research on Aging, Novato, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091711550579000_2026.09.08.750001v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12143"},{"key":"2026091711550579000_2026.09.08.750001v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2014.10.002"},{"key":"2026091711550579000_2026.09.08.750001v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2022.10.004"},{"key":"2026091711550579000_2026.09.08.750001v1.4","doi-asserted-by":"crossref","unstructured":"Robison, L. 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