Periodic Therapeutic Phlebotomy Mitigates Systemic Aging Phenotypes by Promoting Bone Marrow Function

ABSTRACT Aging is the primary risk factor for numerous chronic diseases, making the identification of safe and effective anti‐aging strategies a critical focus in biomedical research. Heterochronic parabiosis by blood exchange shows that the exchange interaction between young and old plasma can exert anti‐aging effects through exchange of bloodborne factors. However, the limited plasma source greatly affects clinical translation. Here, we demonstrate that periodic therapeutic phlebotomy in D‐galactose‐induced aging models exerts significant and comprehensive anti‐aging effects, which is reflected by a notable improvement in aging‐associated behavioral deficits and neurogenesis, a significant decrease in the level of circulating senescence‐associated secretory phenotypes, and an obvious mitigation of aging‐associated structural degradation and molecular alterations within the muscle, bone, liver, kidney, and nervous systems. Mechanistically, periodic therapeutic phlebotomy induces bone marrow microenvironment restoration through functional rescue of mesenchymal stem cells and endothelial cells, thereby reestablishing balanced hematopoietic homeostasis. This hematopoietic revitalization subsequently drives systemic improvements in peripheral blood composition and function. In conclusion, our work provides preliminary evidence suggesting that periodic therapeutic phlebotomy exerts anti‐aging effects by restoring bone marrow function and mitigating aging phenotypes, subsequently driving peripheral blood functional restoration. Given its technical simplicity and safety profile, this periodic therapeutic phlebotomy strategy will hold potential to pave the way for clinical translation.