Longevity Protein LAV-BPIFB4 Curbs Fat Tissue Inflammation to Shield Blood Vessels

Obesity is now recognized as a chronic low-grade inflammatory state, and the visceral adipose tissue (VAT) that accumulates with excess caloric intake is a major driver of systemic inflammation, endothelial dysfunction, and atherosclerosis. Conventional anti-inflammatory treatments can paradoxically worsen fat tissue dysfunction, creating an unmet need for agents that specifically recalibrate adipose inflammatory signaling. The LAV-BPIFB4 protein — a genetic variant enriched in long-lived individuals (centenarians and near-centenarians) — has previously been shown via gene therapy to restore vascular and cardiac function and reduce systemic inflammation in aging mouse models. This study asked whether orally administered recombinant human LAV-BPIFB4 (rhLAV-BPIFB4) could extend those protective effects to an obesity-driven atherosclerosis context.

Using ApoE-knockout mice — a standard model of atherosclerosis — the team fed animals a Western high-fat diet (60% fat) with or without oral rhLAV-BPIFB4 delivered by gavage every three days, alongside standard-diet controls. After four weeks, the researchers assessed aortic plaque composition, circulating cytokine profiles, epididymal white adipose tissue (eWAT) immune infiltration, pre-adipocyte secretory profiles, and ex vivo vascular reactivity of mesenteric arteries exposed to fat-tissue conditioned media.

Key vascular findings revealed that rhLAV-BPIFB4 treatment significantly reduced ICAM-1 expression (a marker of endothelial activation) and CD68+ macrophage infiltration in aortic sections, while preserving α-SMA-positive smooth muscle cells — indicating attenuated atherosclerotic progression and plaque remodeling. Notably, these benefits occurred without any reduction in total adiposity, showing the protein acts through inflammatory pathways rather than metabolic weight reduction.

At the systemic level, treated mice showed reduced circulating IL-1α, IL-1β, TNF-α, GM-CSF, MCP-1, and IL-17, with a modest increase in anti-inflammatory IL-10. At the local adipose tissue level, multiplex ELISA of 24-hour pre-adipocyte supernatants from eWAT recapitulated this anti-inflammatory shift, with reduced IL-1α, IL-1β, TNF-α, IL-6, GM-CSF, MCP-1, and IL-17. Infiltration of CD38+CD45+ inflammatory leukocytes into eWAT was also significantly reduced in treated mice. In the critical ex vivo experiment, conditioned media from eWAT of rhLAV-treated mice restored acetylcholine-induced vasorelaxation in dysfunctional arteries from HFD mice — a functionally compelling demonstration that the protein's anti-inflammatory action in fat tissue directly translates to improved endothelial function.

These results collectively suggest that oral LAV-BPIFB4 supplementation could serve as a novel therapeutic strategy targeting the adipose-inflammation-vascular axis, complementing rather than replacing lifestyle interventions. The approach is particularly notable because it mimics a naturally occurring longevity-associated genetic advantage and operates independently of body weight reduction.