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These preclinical models have revealed that both pro-geronic and anti-geronic signals in blood can\u00a0modulate neuroinflammation, neurovascular health, and cognitive resilience. However, despite their experimental promise, the clinical\u00a0translation of these findings, particularly through plasma-based interventions in humans, remains fraught with uncertainty. This review\u00a0critically examines the strengths and limitations of parabiosis-based paradigms as platforms for discovery, contrasts them with early\u00a0human plasma infusion studies, and evaluates the current biological, medical, and ethical challenges associated with young plasma\u00a0therapies. Therapeutic plasma exchange has also emerged as a potential rejuvenation strategy, but its mechanisms, efficacy, and longterm\u00a0safety remain incompletely understood. We argue that future progress in systemic rejuvenation will depend on precise,\u00a0mechanistically informed interventions\u2014rather than broad, premature applications of plasma therapies, which require further\u00a0validation through rigorous scientific investigation.<\/jats:p>","DOI":"10.1007\/s11357-026-02136-8","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T21:42:22Z","timestamp":1771623742000},"page":"4571-4584","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Plasma-based strategies for systemic rejuvenation: critical perspectives on clinical translation"],"prefix":"10.1007","volume":"48","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"}]},{"given":"Anna","family":"Ungvari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Tordai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek M.","family":"Huffman","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6035-6039","authenticated-orcid":false,"given":"Zoltan","family":"Ungvari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Csiszar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"2136_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2025.07.039","author":"S Liu","year":"2025","unstructured":"Liu S, Wang S, Dong Y, Yang S, Yao C. 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