Endothelial C/EBPß/AEP Pathway Drives Vascular Deterioration and Systemic Aging
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 ß (C/EBPß)/asparagine endopeptidase (AEP) pathway in aging vascular endothelial cells contributes to vascular degeneration and lifespan reduction. Endothelial-specific C/EBPß 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+) biosynthesis, resulting in systemic NAD? depletion and senescence that elicits both central and peripheral vascular dysfunction and ultimately systemic aging. Genetic ablation of AEP or expression of AEP-resistant NAMPT N136A mutant significantly ameliorated vascular aging and extended lifespan in endothelial-specific Tie 2-C/EBPß transgenic mice. Pharmacologically, AEP inhibitor CP#11A or nicotinamide mononucleotide (NMN) supplementation alleviated age-related vascular decline, with CP#11A showing superior efficacy. These findings support a model in which endothelial senescence contributes to vascular dysfunction and systemic aging mediated by C/EBPß/AEP signaling, and establish C/EBPß/AEP as a therapeutic target to preserve vascular integrity and mitigate systemic frailty in aging populations.
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 ß (C/EBPß)/asparagine endopeptidase (AEP) pathway in aging vascular endothelial cells contributes to vascular degeneration and lifespan reduction. Endothelial-specific C/EBPß 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+) biosynthesis, resulting in systemic NAD? depletion and senescence that elicits both central and peripheral vascular dysfunction and ultimately systemic aging. Genetic ablation of AEP or expression of AEP-resistant NAMPT N136A mutant significantly ameliorated vascular aging and extended lifespan in endothelial-specific Tie 2-C/EBPß transgenic mice. Pharmacologically, AEP inhibitor CP#11A or nicotinamide mononucleotide (NMN) supplementation alleviated age-related vascular decline, with CP#11A showing superior efficacy. These findings support a model in which endothelial senescence contributes to vascular dysfunction and systemic aging mediated by C/EBPß/AEP signaling, and establish C/EBPß/AEP as a therapeutic target to preserve vascular integrity and mitigate systemic frailty in aging populations.
European Bioinformatics Institute