The Aging Blood: Cellular Origins, Circulating Drivers, and Therapeutic Potential

ABSTRACT Aging is a complex and systemic biological process. As a crucial conduit linking all organs and tissues, the blood system not only reflects systemic aging phenotypes but may also actively drive the progression of organismal aging. In recent years, a series of heterochronic parabiosis and plasma transfusion experiments have revealed that exposure to young blood can restore the function of multiple organs in aged individuals, spurring growing interest in the concept of “blood‐based antiaging.” Studies have identified a range of rejuvenating factors in young plasma—such as GDF11, TIMP2, and PF4—while aged blood is enriched in pro‐aging signals, including CCL11, C1q, β2‐microglobulin, and components of the senescence‐associated secretory phenotype (SASP). These findings suggest that blood serves not only as a vehicle for youth‐promoting cues but also as a reservoir of aging‐inducing signals. Further research has shown that hematopoietic stem cells (HSCs), the root of the hematopoietic system, undergo functional decline, myeloid‐biased differentiation, and clonal hematopoiesis during aging—key features that are tightly linked to immunosenescence, inflammaging, and multi‐organ dysfunction. Transplantation of young HSCs has been demonstrated to extend lifespan and improve neurological, cardiac, and immune functions, highlighting their promising role in antiaging interventions. This review aims to systematically outline the development of blood‐based rejuvenation research, focusing on the regulatory roles of circulating aging‐related factors and the mechanistic underpinnings of HSC aging, and to explore future strategies and translational prospects of targeting the hematopoietic system in aging intervention.