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While cell-autonomous mechanisms that occur within cells, independent of external signals from neighboring cells or systemic factors, account for some aspects of aging, they cannot explain the entire aging process. Non-autonomous, paracrine and endocrine, pathways also play a crucial role in orchestrating brain and vascular aging. The systemic milieu modulates aging through pro-geronic and anti-geronic circulating factors that mediate age-related decline or confer rejuvenative effects. This review explores the impact of systemic factors on cerebrovascular and brain aging, with a particular focus on findings from heterochronic parabiosis, blood exchange, and plasma transfer experiments. We discuss how these factors influence fundamental cellular and molecular processes of aging and impact cerebrovascular endothelial function, neurovascular coupling mechanisms, blood\u2013brain barrier integrity, neuroinflammation, capillary density, and amyloid pathologies, with significant consequences for cognitive function. Additionally, we address the translational potential and challenges of modifying the systemic milieu to promote brain health and prevent age-related cognitive impairment.<\/jats:p>","DOI":"10.1007\/s11357-025-01657-y","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:52:15Z","timestamp":1747961535000},"page":"6207-6376","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Impacts of systemic milieu on cerebrovascular and brain aging: insights from heterochronic parabiosis, blood exchange, and plasma transfer experiments"],"prefix":"10.1007","volume":"47","author":[{"given":"Rafal","family":"Gulej","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Patai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5053-2828","authenticated-orcid":false,"given":"Anna","family":"Ungvari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Kallai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Tarantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andriy","family":"Yabluchanskiy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek M.","family":"Huffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Conboy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina M.","family":"Conboy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Kivim\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Csiszar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoltan","family":"Ungvari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"1657_CR1","unstructured":"United Nations, Department of Economic and Social Affairs, Population Division: World Population Ageing 2022. 2020. https:\/\/www.un.org\/development\/desa\/pd\/sites\/www.un.org.development.desa.pd\/files\/undesa_pd-2020_world_population_ageing_highlights.pdf."},{"key":"1657_CR2","unstructured":"Alzheimer\u2019s Disease International (ADI) - World Alzheimer Report 2024. https:\/\/www.alzint.org\/u\/World-Alzheimer-Report-2024.pdf."},{"key":"1657_CR3","doi-asserted-by":"publisher","unstructured":"Zlokovic BV, Gottesman RF, Bernstein KE, Seshadri S, McKee A, Snyder H, Greenberg SM, Yaffe K, Schaffer CB, Yuan C, Hughes TM, Daemen MJ, Williamson JD, Gonzalez HM, Schneider J, Wellington CL, Katusic ZS, Stoeckel L, Koenig JI, Corriveau RA, Fine L, Galis ZS, Reis J, Wright JD, Chen J. 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