Endothelial C/EBPβ/AEP pathway drives vascular deterioration and systemic aging.

Bowei Li, Shuke Nie, Mengmeng Wang, Jiawei An, Zhengjiang Qian, Xin Meng, Laura E Edgington-Mitchell, Zhentao Zhang, Xifei Yang, Keqiang Ye

Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China. · pubmed

Paper

Abstract

Age-related microvascular dysfunction disrupts nutrient homeostasis and waste clearance, leading to organ failure. However, a critical gap remains in our understanding of the specific molecular drivers of vascular deterioration and how they orchestrate organism-wide aging. Here, we identify progressive activation of the CCAAT/enhancer-binding protein β (C/EBPβ)/asparagine endopeptidase (AEP) pathway in aging vascular endothelial cells contributes to vascular degeneration and lifespan reduction. Endothelial-specific C/EBPβ or AEP overexpression accelerated vascular aging and shortened lifespan in mice. Mechanistically, AEP mediates proteolytic cleavage of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (oxidised form, NAD

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Research summary

The paper claims that the C/EBPβ/AEP pathway in endothelial cells drives vascular aging and systemic lifespan reduction by cleaving NAMPT and depleting NAD+. This is highly relevant because it identifies a specific, causal molecular mechanism in a key cell type (endothelium) that links local vascular deterioration to organism-wide aging and lifespan, offering a potential target for interventions aimed at extending healthspan and lifespan rather than just treating symptoms.

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