{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:33:41Z","timestamp":1793043221376,"version":"4.5.0"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>\n                    Aging remains the predominant risk factor for Alzheimer\u2019s disease (AD) and other neurodegenerative disorders, yet the mechanisms linking systemic aging to brain dysfunction remain incompletely understood. Cellular senescence, a state of stable cell-cycle arrest coupled with metabolic and secretory reprogramming, has emerged as a pivotal and context-dependent driver of brain aging. Accumulation of senescent glial cells (astrocytes, microglia, and oligodendrocyte progenitors) and emerging evidence of \u201cneurescence\u201d in post-mitotic neurons contribute to neuroinflammation, impaired proteostasis, and synaptic dysfunction. This review synthesizes molecular, cellular, and translational findings that reframe senescence as an active process shaping brain vulnerability. We discuss SASP-mediated neurotoxicity, crosstalk among senescent glial subtypes, and context-specific pathways (NF-\u03baB, p38 MAPK, mTOR, cGAS\u2013STING) as therapeutic targets. Senomorphic and senolytic strategies, alongside emerging systemic interventions such as therapeutic plasma exchange with albumin replacement, are evaluated for their potential to mitigate senescence burden and restore homeostasis. Integrating evidence from fluid, imaging, and multi-omic biomarkers, we highlight how senescence can now be monitored\n                    <jats:italic>in vivo<\/jats:italic>\n                    and stratified across disease stages. Multi-omic and spatial transcriptomic data reveal that central and peripheral senescence signatures only partially overlap, suggesting bidirectional communication across the brain\u2013body axis. This systemic dimension raises key questions about whether modifying peripheral senescence or proteostasis could reshape CNS trajectories. However, key uncertainties remain, particularly regarding the causal role of senescence in human neurodegeneration, the specificity of current biomarkers, and the distinction between adaptive versus maladaptive senescence responses. Notably, direct evidence linking senescent cells to functional alterations in the human brain microenvironment remains limited. This review distinguishes itself from prior literature by integrating a multi-scale brain\u2013body axis perspective, combining molecular, cellular, and systemic evidence to propose senescence as a bidirectional and context-dependent driver of neurodegeneration rather than a purely cell-autonomous process.\n                  <\/jats:p>","DOI":"10.3389\/fncel.2026.1805691","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T04:22:12Z","timestamp":1779164532000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Cellular senescence in brain aging and neurodegeneration: from molecular mechanisms to translational opportunities"],"prefix":"10.3389","volume":"20","author":[{"given":"Yahveth","family":"Cantero-Fortiz","sequence":"first","affiliation":[{"name":"Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya","place":["Barcelona, Spain"]},{"name":"Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Butler","sequence":"additional","affiliation":[{"name":"Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya","place":["Barcelona, Spain"]},{"name":"The George Institute for Global Health, Imperial College London","place":["London, United Kingdom"]},{"name":"Department of Brain Sciences, Imperial College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Montalb\u00e1n","sequence":"additional","affiliation":[{"name":"Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya","place":["Barcelona, Spain"]},{"name":"Vall d'Hebron Hospital Universitari","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merc\u00e8","family":"Boada","sequence":"additional","affiliation":[{"name":"Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya","place":["Barcelona, Spain"]},{"name":"Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.1038\/s43587-025-00965-4","article-title":"Plasma proteomic associations with Alzheimer's disease endophenotypes","volume":"5","author":"Afshar","year":"2025","journal-title":"Nat. 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