# Neuronal C/EBPβ Shortens the Lifespan via Inactivating NAMPT

## TL;DR

This study shows that increased C/EBPβ in neurons causes aging by reducing NAD+ levels, and blocking AEP or using NAMPT mutants or inhibitors can extend lifespan and improve aging symptoms.

## Contribution

The paper identifies C/EBPβ and AEP as key drivers of neuronal aging and proposes AEP inhibition as a novel therapeutic strategy to combat aging.

## Key findings

- Neuronal C/EBPβ upregulation leads to NAMPT fragmentation and NAD+ depletion, causing neuronal senescence and reduced lifespan.
- AEP knockout or NAMPT N136A mutant expression extends the lifespan of Thy 1-C/EBPβ transgenic mice.
- AEP inhibitor #11a improves cognitive and motor impairments and increases life expectancy more effectively than NMN.

## Abstract

The brain plays a central role in aging and longevity in diverse model organisms. Morphological and functional alteration in the aging brain elicits age‐associated neuronal dysfunctions. However, the primary mechanism deteriorating the brain functions to regulate the aging process remains incompletely understood. Here, it is shown that neuronal CCAAT/enhancer binding protein β (C/EBPβ) escalation during aging dictates the frailty and lifespan via inactivating nicotinamide phosphoribosyltransferase (NAMPT). Upregulated C/EBPβ drives neuronal senescence and neuronal loss, associated with NAMPT fragmentation by active asparagine endopeptidase (AEP), leading to nicotinamide adenine dinucleotide (NAD+) depletion. Knockout of AEP or expression of AEP‐resistant NAMPT N136A mutant significantly elongates the lifespan of neuronal‐specific Thy 1‐C/EBPβ transgenic mice. Overexpression of the C. elegans C/EBPβ ortholog cebp‐2 in neurons shortens lifespan and decreases NAD+ levels, which are restored by feeding nicotinamide mononucleotide (NMN) or AEP inhibitor #11a. Feeding NMN or #11a substantially ameliorates the cognitive and motor impairments of Thy 1‐C/EBPβ mice and increases the life expectancy. Notably, #11a demonstrates a better therapeutic effect than NMN in improving aging phenotype in Thy 1‐C/EBPβ transgenic mice, which show accelerated aging features. Hence, blockade of AEP via therapeutic intervention may provide an unprecedented strategy for fighting aging and various age‐associated diseases.

Schematic diagram illustrating the mechanism of shortened lifespan in Thy 1‐C/EBPβ transgenic mice and intervention strategies. Briefly, C/EBPβ/AEP escalation in the aging brain triggers NAMPT fragmentation and NAD+ depletion. Knockout of AEP from Thy 1‐C/EBPβ Tg/Tg mice ameliorates cognitive impairments and elongates the lifespan. AEP‐resistant NAMPT N136A mutant rescues the cognitive dysfunction and short lifespan of Thy 1‐C/EBPβ Tg/Tg mice. AEP inhibitor #11a administration alleviates cognitive deficits and life expectancy of Thy 1‐C/EBPβ Tg/Tg mice and C. elegans.