An IGF signaling–regulated mechanism that protects from β-amyloid (Aβ) toxicity is conserved from worms to mammals. Reduction of insulin/IGF-1 signaling is a strongly conserved mechanism of life-span extension in worms, flies, and mammals.

elegans, neural excitation increases with age and inhibition of excitation increases longevity, for which the transcription factors REST (RE1 silencing transcription factor)/FOXO (Forkhead Box O) are indispensable, and they are up-regulated in humans with extended longevity and they repress excitation-related genes ( 6). Ablation in the Drosophila brain of specific neurosecretory cells that produce insulin-like peptides extends life span ( 5). In the nematode Caenorhabditis elegans, deletion of specific sensory or neurosecretory neurons alters life span ( 1– 3), and life-span extension from reduced insulin/insulin-like growth factor (IGF)–like signaling can be reversed by restoring function specifically in neurons ( 4). The nervous system plays a critical role in the regulation of aging. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPβ/AEP pathway. C/EBPβ and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. CEBP-2 or LGMN-1 reduces daf-2 mutant–elongated life span and diminishes daf-16–induced longevity. Overexpression of CEBP-2 or LGMN-1 (AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span.

C/EBPβ selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction. Here, we show that C/EBPβ, an Aβ and inflammatory cytokine–activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose–dependent manner in neuronal C/EBPβ transgenic mice. However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer’s disease (AD).

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