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Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circulating bone marrow (BM)\u2010derived thymus seeding progenitors (TSPs) that differentiate into early T\u2010cell progenitors (ETPs). We find that ETP cellularity declines as early as 3\u2009months (3MO) of age in mice. This initial ETP reduction could reflect changes in thymic stromal niches and\/or pre\u2010thymic progenitors. Using a multicongenic progenitor transfer approach, we demonstrate that the number of functional TSP\/ETP niches does not diminish with age. Instead, the number of pre\u2010thymic lymphoid progenitors in the BM and blood is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM lymphoid progenitors and in ETPs diminishes by 3MO, suggesting reduced niche quality in the BM and thymus contribute to the early decline in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to an initial reduction in ETPs in young adulthood, setting the stage for progressive age\u2010associated thymus involution.<\/jats:p>","DOI":"10.1111\/acel.13870","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T04:35:41Z","timestamp":1684902941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The initial age\u2010associated decline in early T\u2010cell progenitors reflects fewer pre\u2010thymic progenitors and altered signals in the bone marrow and thymus microenvironments"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9478-7518","authenticated-orcid":false,"given":"Jayashree","family":"Srinivasan","sequence":"first","affiliation":[{"name":"Department of Molecular Biosciences The University of Texas at Austin  Austin Texas United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anusha","family":"Vasudev","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis The University of Texas MD Anderson Cancer Center  Houston Texas United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Shasha","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division Fred Hutchinson Cancer Center  Seattle Washington United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary J.","family":"Selden","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences The University of Texas at Austin  Austin Texas United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Encarnacion","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis The University of Texas MD Anderson Cancer Center  Houston Texas United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie","family":"LaFleur","sequence":"additional","affiliation":[{"name":"Center for Biomedical Informatics and Statistics The University of Arizona  Tucson Arizona United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shripad A.","family":"Sinari","sequence":"additional","affiliation":[{"name":"Center for Biomedical Informatics and Statistics The University of Arizona  Tucson Arizona United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Krueger","sequence":"additional","affiliation":[{"name":"Molecular Immunology Justus\u2010Liebig\u2010University Giessen  Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen R.","family":"Richie","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis The University of Texas MD Anderson Cancer Center  Houston Texas United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1697-1755","authenticated-orcid":false,"given":"Lauren I. 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