Science advancesSep 16, 2026

A blood vessel cell pathway linked to blood vessel decline and overall aging

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 17, 2026

Abstract

Progressive activation of the C/EBPβ/AEP pathway in aging endothelial cells is associated with vascular degeneration and reduced lifespan.

Overexpression of C/EBPβ or AEP in mice accelerated vascular aging and shortened lifespan.
AEP is involved in the breakdown of NAMPT, a key enzyme for producing NAD+, leading to systemic NAD+ depletion.
Systemic NAD+ depletion and cellular aging contribute to dysfunction in both central and peripheral vascular systems.
Genetic removal of AEP or introduction of an AEP-resistant NAMPT mutant improved vascular aging and extended lifespan in specific mouse models.
Pharmacological inhibition of AEP or supplementation with nicotinamide mononucleotide (NMN) reduced age-related vascular decline, with AEP inhibitor CP#11A being more effective.

Simplified

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⁺) 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/EBPβ 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/EBPβ/AEP signaling, and establish C/EBPβ/AEP as a therapeutic target to preserve vascular integrity and mitigate systemic frailty in aging populations.

Full Text

Full text is available at the source.

View Full Text ↗

A blood vessel cell pathway linked to blood vessel decline and overall aging

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the longevity & aging brief