Researchers identify cholecystokinin signaling as neuronal healthspan regulator in C. elegans

A study in Genetics reports that NLP-12/cholecystokinin signaling actively preserves sensory dendritic structure and proprioceptive locomotion in aging C. elegans, offering a conserved pathway for extending neuronal healthspan.

Researchers from the Medical College of Wisconsin published a study in Genetics demonstrating that NLP-12/cholecystokinin-like neuropeptide signaling stabilizes sensory dendritic structure and protects proprioceptive function during aging in C. elegans.

The study reported that aging leads to a decline in extracellular delivery of NLP-12 and increased retention within the soma of the DVA interneuron, resulting in abnormal higher-order dendritic branching in PVD sensory neurons and corresponding motor deficits.

Loss-of-function mutants of nlp-12 showed accelerated dendritic branching and earlier locomotive decline, whereas nlp-12 overexpression attenuated dendritic branching in aged adults without extending overall lifespan, showing a neuron-focused effect on healthspan.

The neuroprotective effect downstream of NLP-12 was shown to require both cholecystokinin receptor homologs, CKR-1 and CKR-2.

Introduction of human cholecystokinin rescued the PVD dendritic branching defect and partially improved proprioceptive patterning in nlp-12 mutant worms, indicating a conserved functional pathway.

The findings establish a specific endogenous signaling pathway that actively maintains neuronal structural integrity over an adult lifespan.

By showing that nlp-12 overexpression protects dendritic structure without extending lifespan, the study suggests that neuronal healthspan can be decoupled from systemic aging rates.

The functional rescue of C. elegans deficits by human cholecystokinin provides a biological rationale for examining cholecystokinin receptor signaling in mammalian models of sensory and motor decline.

The identification of CKR-1 and CKR-2 receptor homologs as mediators of age-associated neuroprotection points to cholecystokinin receptor agonists as possible research targets for age-related sensory and motor decline.

There are currently no active clinical-stage programs in the longevity sector targeting the NLP-12/cholecystokinin pathway, representing an open biological mechanism for early-stage drug discovery.

The focus on neuronal healthspan rather than lifespan extension aligns with growing regulatory and clinical interest in tissue-specific functional preservation over systemic longevity therapeutics.

Preclinical validation of human cholecystokinin signaling and receptor agonists in mammalian models of age-related sensory-motor decline and dendritic degeneration.