The vascular protease AEP cleaves the key NAD+ synthesis enzyme with age and drives systemic aging: blocking the cleavage extended mouse lifespan more than NAD+ supplements
The vascular protease AEP cleaves the key NAD+ synthesis enzyme with age and drives systemic aging: blocking the cleavage extended mouse lifespan more than NAD+ supplements
On September 16, Science Advances published a paper by Keqiang Ye's team showing that the C/EBPβ/AEP pathway intensifies with age in endothelial cells lining the blood vessels, and the protease AEP cleaves NAMPT, the enzyme that produces NAD+. Activating this pathway solely in the vasculature of healthy young mice was sufficient to impair blood flow and shorten their lifespan by nearly a third. Eliminating the cleavage itself, either genetically or pharmacologically, restored near-normal function.
Keqiang Ye's team has studied the protease AEP for over a decade. He discovered it in 2015 and named it "delta-secretase" for its role in destroying neurons in Alzheimer's disease. By 2022, the group had shown that the same C/EBPβ/AEP pathway shortens mouse lifespan through neuronal death, and in 2025 they identified the precise mechanism: in brain neurons, AEP cleaves the same NAMPT. Endothelial cells line the inner surface of blood vessels in virtually every tissue, so the team set out to test whether the same pathway operates there as well. If it does, it could represent a shared cause behind the synchronized aging of multiple systems, from muscle perfusion to brain function. The new paper in Science Advances confirms exactly that.
In both humans and mice, C/EBPβ/AEP pathway activity in the vascular endothelium, the thin cell layer on the inner surface of blood vessels, increases with age. To test whether this increase alone is sufficient to drive aging, the authors engineered mice in which AEP is overactive only in the endothelium. These otherwise healthy young animals developed impaired muscle blood flow and increased permeability of the blood-brain barrier, the membrane that normally prevents foreign substances in the blood from entering the brain. Median lifespan fell from 769 to 518 days in males and from 807 to 520 in females, a reduction of nearly one third.
The damage traced to a single specific site: AEP cleaves NAMPT at amino acid position 136, and the cleaved enzyme loses its ability to convert nicotinamide back into NAD+. Replacing NAMPT with a cleavage-resistant version restored NAD+ production more effectively than simply increasing the amount of NAMPT, confirming that the harm comes specifically from the cleavage. In a more aggressive model with stronger pathway activation, median male lifespan dropped to 390 days versus 804 in healthy age-matched controls. Deleting the AEP gene in these same mice restored lifespan nearly to normal, to 754 days.
The laboratory already has an experimental AEP inhibitor, CP#11A. Mice with accelerated aging were started on either CP#11A or the NAD+ precursor nicotinamide mononucleotide (NMN) at mid-life, at 10 months of age. Median male lifespan rose from 521 days in controls to 673 with NMN and to 718 with CP#11A. The AEP inhibitor outperformed the NAD+ supplement on nearly every measure, including NAD+ levels, frailty, memory, and endurance.
In humans, NAD+ precursor supplements (the same NMN and nicotinamide riboside) have produced inconsistent results in clinical trials: some show improved insulin sensitivity, others show no effect. The authors attribute this to the same mechanism. The protease continually destroys the machinery that produces NAD+, and supplying more substrate does not repair it. The necessary intervention is to prevent the cleavage itself by blocking AEP.
Mice kept on CP#11A throughout life were monitored with blood and urine panels: liver and kidney function remained intact, tumor incidence did not increase, and the compound crosses the blood-brain barrier. The effect has so far been demonstrated in mice with engineered accelerated aging. Testing in naturally aged animals lies ahead.