CD38 Inhibition Ameliorates Age-Related Cognitive Decline via a Choroid Plexus–Cerebrospinal Fluid–Hippocampus Axis

Abstract Age-related cognitive decline represents a major and unresolved challenge of human aging. Here, we identify the NAD⁺-consuming enzyme CD38 as a central regulator of cognitive aging acting through a choroid plexus–cerebrospinal fluid (CSF)–hippocampus axis. CD38 expression increases with age and localizes primarily to pericytes in the choroid plexus, where it depletes NAD⁺, impairs mitochondrial function, and promotes cellular senescence. Genetic ablation or pharmacological inhibition of CD38 restores NAD⁺ levels, suppresses senescence markers, and improves choroid plexus function, resulting in a rejuvenated CSF proteomic and metabolomic profile characterized by reduced inflammatory signaling and enhanced neurotrophic support. These changes propagate to the hippocampus, reversing age-related transcriptional signatures and enhancing synaptic plasticity. A novel, brain-penetrant CD38 inhibitor, NTX-748, reproduced the benefits of CD38 deficiency—elevating systemic and brain NAD⁺ levels, improving long-term potentiation, and enhancing multiple domains of cognition in aged mice. Collectively, these findings identify the choroid plexus as a metabolic gatekeeper of brain aging and establish CD38 inhibition as a promising therapeutic strategy to promote cognitive resilience and healthy brain aging.