Neuronal C/EBPβ Shortens the Lifespan via Inactivating NAMPT

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.