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Beyond its role in circulation, the vascular system acts as a dynamic interface between tissues, influencing countless physiological functions such as tissue regeneration and repair, immune responses, and metabolic balance. Importantly, age\u2010related vascular impairment\u2014characterized by a peculiar set of endothelial aging hallmarks\u2014exacerbates age\u2010related diseases (ARDs) such as cardiovascular disorders, neurodegeneration, chronic kidney disease, sarcopenia, and osteoporosis. This review combines basic concepts of angioscience and aging biology with translational interventions to devise clinical strategies promoting a functional rejuvenation of old and compromised blood vessels, fostering the prevention, delay or treatment of ARDs. Starting from the description of the cellular and molecular mechanisms driving vascular aging, a cutting\u2010edge perspective on the organ\u2010specific vascular impairment and its impact on tissue function is offered. Given the central role of the vasculature in aging, how targeting vascular aging through pharmacological, genetic, and lifestyle interventions holds promise for mitigating its systemic consequences and improving healthspan is discussed. Finally, how the combination of animal models (e.g., parabiosis) and novel microphysiological systems, coupled with multi\u2010omics and artificial intelligence\u2010driven analyses, is advancing the field toward the identification of strategies that promote vascular resilience and extend healthspan, addressing one of the most pressing biomedical challenges of a worldwide aging population is highlighted.<\/jats:p>","DOI":"10.1002\/advs.202508659","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T05:49:55Z","timestamp":1762408195000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Microvascular Health as a Key Determinant of Organismal Aging"],"prefix":"10.1002","volume":"12","author":[{"given":"Mattia","family":"Cenciarini","sequence":"first","affiliation":[{"name":"Regenerative Medicine Division Institute for Translational Research (IRT) Faculty of Biomedical Sciences Universit\u00e0 della Svizzera italiana (USI) and Ente Ospedaliero Cantonale (EOC) Bellinzona 6500 Ticino Switzerland"},{"name":"Euler Institute Faculty of Biomedical Sciences Universit\u00e0 della Svizzera italiana Lugano 6900 Ticino Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Uccelli","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Division Institute for Translational Research (IRT) Faculty of Biomedical Sciences Universit\u00e0 della Svizzera italiana (USI) and Ente Ospedaliero Cantonale (EOC) Bellinzona 6500 Ticino Switzerland"},{"name":"Euler Institute Faculty of Biomedical Sciences Universit\u00e0 della Svizzera italiana Lugano 6900 Ticino Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mangili","sequence":"additional","affiliation":[{"name":"Istituto Dalle Molle di Studi sull'Intelligenza Artificiale (IDSIA) SUPSI Lugano 6900 Ticino Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Grunewald","sequence":"additional","affiliation":[{"name":"Faculty of Medicine The Hebrew University of Jerusalem Jerusalem 9190500 Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4620-3500","authenticated-orcid":false,"given":"Simone","family":"Bersini","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Division Institute for Translational Research (IRT) Faculty of Biomedical Sciences Universit\u00e0 della Svizzera italiana (USI) and Ente Ospedaliero Cantonale (EOC) Bellinzona 6500 Ticino Switzerland"},{"name":"Euler Institute Faculty of Biomedical Sciences Universit\u00e0 della Svizzera italiana Lugano 6900 Ticino Switzerland"},{"name":"Servizio di Ortopedia e Traumatologia Ente Ospedaliero Cantonale Lugano 6900 Ticino Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"e_1_2_10_1_1","unstructured":"Blueprint \u2013 Blueprint Bryan Johnson [Internet]. 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