Krishna, M.; Franitza, A. L.; E, L.

Despite significant progress in understanding the molecular processes of aging-associated neurodegeneration, the upstream mechanisms driving neuronal aging remain elusive. Here, we investigate the potential regulatory roles of non-neural tissues in neuronal aging, using Caenorhabditis elegans PVD polymodal neuron as a model. We find that cutaneous PVD neurons develop progressive excessive dendritic branching during normal aging, functionally correlated with age-related deficits in proprioception. Our study reveals that age-related reduction in skin collagens, a common change across species, triggers the aging process of PVD. Specifically, loss-of-function mutations or adulthood-specific RNAi knockdown of skin collagen genes, dpy-5 or col-120, which are downregulated with age, induce an early onset of PVD excessive dendritic branching and proprioception deficits. Overexpressing dpy-5 or col-120 mitigates the development of excessive branching without affecting lifespan, suggesting a skin collagens\' role in promoting healthspan rather than longevity. Notably, neither dpy-5 or col-120 is not involved in aging-associated dendritic beading, another degenerative phenotype in PVD associated with harsh touch response deficits. Moreover, dpy-5 mutation induces ectopic branching in ALM, but does not affect PLM, two other cutaneous sensory neurons. Finally, we identify rig-3, a neuronal Immunoglobulin Superfamily member not expressed in PVD or the skin, functioning in the same pathway as skin collagen genes to preserve PVD neuron integrity during aging. Our findings reveal the causative role of age-related reduction in skin collagens in neuronal aging, selectively impacting distinct neuron subtypes and structures. This study underscores the importance of exploring multi-tissue strategies to comprehensively address the complexities of neuronal aging.