NLP-12/Cholecystokinin signaling stabilizes sensory dendritic structure and protects neuronal healthspan in Caenorhabditis elegans

Aging selectively degrades neuronal structure and function, yet the signals that actively preserve neuronal integrity over adult life remain incompletely defined. In Caenorhabditis elegans, the PVD sensory neuron develops progressive excessive higher-order dendritic branching during normal aging that correlates with declines in proprioceptive locomotion. Using this system as a quantitative in vivo readout of neuronal healthspan, we identify the cholecystokinin-like neuropeptide NLP-12 as a protective signal that preserves PVD homeostasis across adulthood. nlp-12 loss-of-function animals show early-onset excessive branching and earlier declines in proprioceptive function, whereas nlp-12 overexpression reduces excessive branching in aged adults without extending lifespan, indicating a neuron-focused effect on healthspan. Using an NLP-12::mKate reporter and coelomocyte uptake as an in vivo proxy for secretion, we find that aging is associated with reduced extracellular delivery of NLP-12 and increased retention within the soma of the DVA interneuron, where nlp-12 is predominantly expressed. Consistent with a requirement for secretory trafficking, disrupting the NLP-12 signal peptide abolishes the rescue effects of nlp-12 reintroduction in nlp-12 mutants. Additionally, histamine-gated silencing of DVA during adulthood similarly accelerates PVD excessive branching, supporting an ongoing, adult-stage requirement for this pathway. Receptor genetics further show that the ckr-1/GPCR is required for nlp-12 overexpression-mediated neuroprotection in aged animals. Finally, human cholecystokinin can rescue the branching phenotype in nlp-12 mutants, supporting evolutionary conservation. Together, these findings implicate conserved cholecystokinin-like neuropeptide signaling as an adult maintenance mechanism that buffers age-associated decline in neuronal resilience.