Neuronal C/EBPβ Shortens the Lifespan via Inactivating NAMPT

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.