{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:57:50Z","timestamp":1790621870436,"version":"4.1.0"},"posted":{"date-parts":[[2026,5,28]]},"group-title":"Cell Biology","reference-count":22,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH\/NIA","award":["U54AG075941"],"award-info":[{"award-number":["U54AG075941"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R01DK132535"],"award-info":[{"award-number":["1R01DK132535"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30 DK036836"],"award-info":[{"award-number":["P30 DK036836"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["UH3CA275681"],"award-info":[{"award-number":["UH3CA275681"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U54 AG079758"],"award-info":[{"award-number":["U54 AG079758"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R37AG013925"],"award-info":[{"award-number":["R37AG013925"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R33AG061456"],"award-info":[{"award-number":["R33AG061456"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Thomas J Beatson Jr Foundation","award":["2025-020"],"award-info":[{"award-number":["2025-020"]}]},{"name":"the Richard and Susan Smith Family Foundation Award"},{"name":"Hevolution Foundation grant","award":["HF-GRO-23-1199148-3"],"award-info":[{"award-number":["HF-GRO-23-1199148-3"]}]},{"name":"the Connor Fund"},{"name":"Robert J. and Theresa W. Ryan"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Biological aging greatly impacts the body\u2019s ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level.<\/jats:p>\n                <jats:p>Here, we performed single-cell\u2013resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20\u201380) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34\u201369). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A.<\/jats:p>\n                <jats:p>\n                  <jats:italic>CDKN1A<\/jats:italic>\n                  \u207a senescent cells (SnCs) exhibit loss of \u03b2-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast,\n                  <jats:italic>CDKN2A<\/jats:italic>\n                  \u207a SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling.\n                <\/jats:p>\n                <jats:p>\n                  Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive (\n                  <jats:italic>CDKN2A<\/jats:italic>\n                  \u207a) from a maladaptive (\n                  <jats:italic>CDKN1A<\/jats:italic>\n                  \u207a) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.\n                <\/jats:p>","DOI":"10.64898\/2026.05.25.727705","type":"posted-content","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T23:10:14Z","timestamp":1780009814000},"source":"Crossref","is-referenced-by-count":1,"title":["Distinct senescent \u03b2-cell senotypes differentially drive islet aging and dysfunction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1671-3980","authenticated-orcid":false,"given":"Kanako","family":"Iwasaki","sequence":"first","affiliation":[{"name":"Joslin Diabetes Center\/Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5748-7217","authenticated-orcid":false,"given":"Hui","family":"Pan","sequence":"additional","affiliation":[{"name":"Joslin Diabetes Center\/Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7242-3991","authenticated-orcid":false,"given":"Jonathan","family":"Dreyfuss","sequence":"additional","affiliation":[{"name":"Joslin Diabetes Center\/Harvard Medical School, Boston, 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