{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T10:17:42Z","timestamp":1787912262648,"version":"build-2784847793"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG079517"],"award-info":[{"award-number":["R01AG079517"]}],"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":["R01AG095974"],"award-info":[{"award-number":["R01AG095974"]}],"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":["R01AG069206"],"award-info":[{"award-number":["R01AG069206"]}],"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":["R01AG100304"],"award-info":[{"award-number":["R01AG100304"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>\n                    Mammalian tissue function depends on the balance between proliferative, mitotic cell populations and irreplaceable post-mitotic cells. Throughout life, aging progressively disrupts cell type balance and thus tissue function through opposing forces on different cell types. Aging promotes the aberrant proliferation or entry into pro-inflammatory senescent states of mitotic cells, while contributing to the functional erosion and, in vulnerable populations, loss of post-mitotic irreplaceable cells. The divergent age-associated vulnerabilities of mitotic and post-mitotic cells caused by aging generate a case of\n                    <jats:italic>homeostatic conflict<\/jats:italic>\n                    , in which tissue maintenance simultaneously demands the elimination of damaged mitotic cells and the preservation of irreplaceable ones. We examine the concept of\n                    <jats:italic>homeostatic conflict<\/jats:italic>\n                    using the aging brain as an example, and illustrate how the senescence-prone glia expand and acquire SASP-rich transcriptional states, while post-mitotic neurons undergo widespread loss of molecular identity and cell death, resulting in cell type imbalance and consequently tissue dysfunction. Based on the observed\n                    <jats:italic>homeostatic conflict,<\/jats:italic>\n                    we then devise potential context-sensitive therapeutic strategies by combining interventions that protect from ferroptosis to selectively protect irreplaceable cells with interventions that eliminate maladaptive ones to resolve the age-associated cell type imbalance and thus the underlying\n                    <jats:italic>homeostatic conflict<\/jats:italic>\n                    . We present\n                    <jats:italic>homeostatic conflict<\/jats:italic>\n                    as a concept that goes beyond the reductionist view in which numerous isolated processes promote aging in isolation, and provides a logical framework that integrates multiple processes and explains how their interaction drives age-associated dysfunction in a manner instructive to the development of pharmacological combination strategies.\n                  <\/jats:p>","DOI":"10.3389\/fgene.2026.1881856","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:39:50Z","timestamp":1787909990000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Homeostatic conflict as a driver for brain aging"],"prefix":"10.3389","volume":"17","author":[{"given":"Cristian A.","family":"Wulkop-Gil","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biology","place":["La Jolla, CA, United States"]},{"name":"Department of Neuroscience, The Scripps Research Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Petrascheck","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology","place":["La Jolla, CA, United States"]},{"name":"Department of Neuroscience, The Scripps Research Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.3324\/haematol.2011.043018","article-title":"A pilot trial of deferiprone for neurodegeneration with brain iron accumulation","volume":"96","author":"Abbruzzese","year":"2011","journal-title":"Haematologica"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1002\/ana.26770","article-title":"Ferroptosis of microglia in aging human white matter injury","volume":"94","author":"Adeniyi","year":"2023","journal-title":"Ann. 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