Better Understanding the Immunomodulatory Effect of the Longevity Associated Variant of BPIFB4
In recent years, researchers have noted that one variant of the BPIFB4 gene is associated with human longevity. This was discovered in the usual way, by noting that older populations tend to have a higher proportion of individuals carrying the variant than is the case for younger populations. In other words, individuals without the protective variant have an incrementally higher mortality rate. The longevity-associated variant of BPIFB4 appears to reduce cardiovascular dysfunction and mortality, and also reduces the chronic inflammatory signaling characteristic of aging. That slowed cardiovascular aging may or may not be entirely a consequence of the reduced inflammation; that remains to be determined.
Studies in mice have shown similar outcomes, and, interestingly, the BPIFB4 protein is robust enough to deliver orally and still produce benefits. Meanwhile, investigations of the underlying biochemistry of BPIFB4 and its role in the body continues, seeking a better understanding of how exactly it works.
Today's open access paper reports on new findings regarding the way in which BPIFB4 interacts with the immune system, which appears to be mediated via the activities of platelets. Platelets are cell fragments manufactured by megakaryocyte cells; they might be thought of as mini-cells that exhibit the surface features and some of the contents of their megakaryocyte progenitors. The primary purpose of platelets is to produce clotting when needed, but even when that is not happening, platelets are active participants in the complex dance of interactions between cells. Researchers suggest that effects hinge on the degree to which CD47 appears on platelet surface membranes, which offers a possible path to developing a drug to mimic BPIFB4 benefits.
The LAV-BPIFB4-Platelet-CD47 Axis: A Novel Mechanism Associated With Immune Resilience in Longevity
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 lipopolysaccharide. Recombinant LAV-BPIFB4 administration in vivo increased CD47 on murine platelets and reduced, ex vivo, LPS-induced monocyte activation, validating cross-species therapeutic potential. Critically, recombinant LAV-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.