Abstract Experimental models such as heterochronic parabiosis and heterochronic plasma transfer have profoundly advanced our understanding of systemic aging, demonstrating that circulating factors can influence brain, vascular, and immune aging through cell nonautonomous mechanisms. These preclinical models have revealed that both pro-geronic and anti-geronic signals in blood can modulate neuroinflammation, neurovascular health, and cognitive resilience. However, despite their experimental promise, the clinical translation of these findings, particularly through plasma-based interventions in humans, remains fraught with uncertainty. This review critically examines the strengths and limitations of parabiosis-based paradigms as platforms for discovery, contrasts them with early human plasma infusion studies, and evaluates the current biological, medical, and ethical challenges associated with young plasma therapies. Therapeutic plasma exchange has also emerged as a potential rejuvenation strategy, but its mechanisms, efficacy, and longterm safety remain incompletely understood. We argue that future progress in systemic rejuvenation will depend on precise, mechanistically informed interventions—rather than broad, premature applications of plasma therapies, which require further validation through rigorous scientific investigation.
Gulej et al. (2026) studied this question.