The LAV‐BPIFB4‐Platelet‐CD47 Axis: A Novel Mechanism Associated With Immune Resilience in Longevity

ABSTRACT Long‐living individuals (LLIs) possess remarkable genetic resilience, characterized by protective variants that confer immune robustness and resistance to age‐related diseases. The longevity‐associated variant of BPIFB4 (LAV‐BPIFB4), enriched in centenarians, demonstrated pleiotropic benefits including reduced inflammation, cardiovascular protection, and immune system rejuvenation. However, the molecular mechanisms underlying these protective effects remain incompletely understood. Here, we revealed that LAV‐BPIFB4 fundamentally reshaped the immune features of platelets to establish enhanced immunomodulatory capacity through CD47 upregulation. Of note, centenarians displayed an elevated percentage of circulating CD47 + reticulated platelets (RPs), a condition mimicked by LAV‐BPIFB4 carriers which exhibited significantly elevated CD47 levels both on RPs and mature platelets' surface. In agreement with an early acquirement of CD47 overexpression, MEG‐01 megakaryoblastic cells overexpressing LAV‐BPIFB4 produced CD47‐high platelet‐sized particles. Functionally, platelets from LAV carriers suppressed monocyte activation and inflammatory cytokine production through CD47‐dependent mechanisms, selectively reducing p38 MAPK activation while leaving NF‐κB signaling largely unaffected in response to LPS. rhLAV‐BPIFB4 administration in vivo increased CD47 on murine platelets and reduced, ex vivo, LPS‐induced monocyte activation, validating cross‐species therapeutic potential. Critically, rhLAV‐BPIFB4 protein phenocopies genetic effects, rapidly increasing CD47 expression on wild‐type platelets through cytoskeleton‐dependent trafficking mechanisms and conferring enhanced anti‐inflammatory capacity. This might represent a translatable strategy to replicate some of the biological features associated with a longevity‐associated variant beyond genetic carriers. Our findings establish the platelet‐CD47‐monocyte axis as a pivotal pathway for healthy aging and reveal recombinant LAV‐BPIFB4 as a promising therapeutic approach for managing inflammaging and cardiovascular disease by harnessing the immune‐tuning capacity characteristic of exceptional longevity.