Skin Collagen Actively Regulates the Aging of Sensory Neurons

Despite significant progress in revealing molecular and cellular changes in aging nervous system, the upstream mechanisms driving these changes remain elusive. Here, we investigate the regulatory roles of non-neural tissues in neuronal aging, using the cutaneous PVD polymodal neuron in Caenorhabditis elegans as a model. We demonstrate that during normal aging, PVD neurons progressively develop excessive dendritic branching, functionally correlated with age-related proprioceptive deficits. Our study further uncovers that decreased skin collagen expression, a common age-related phenomenon across species, triggers PVD aging. Specifically, loss-of-function mutations or adulthood-specific knockdown of dpy-5 or col-120 , both genes coding for cuticular collagens secreted to the epidermal apical surface, induce early-onset excessive dendritic branching in PVD, and proprioceptive deficits. Overexpressing dpy-5 or col-120 mitigates excessive branching without affecting lifespan, suggesting that skin collagens promote healthspan rather than longevity. Notably, these collagens are not involved in aging-associated dendritic beading, another PVD neurodegenerative phenotype distinctively associated with a different mechanosensitive dysfunction. Skin collagens also specifically affect branching in select sub-classes of sensory neurons. Lastly, we identify rig-3 , a neuronal Immunoglobulin Superfamily member not expressed in PVD, functioning in the same pathway as skin collagen genes to preserve PVD dendritic integrity during aging. These findings reveal an important causative role of age-related skin collagen reduction in neuronal aging, independent of their traditionally recognized involvement in direct structural support for neurons. Our study offers new insights into understanding selective neuron vulnerability in aging and age-related diseases, emphasizing the need for multi-tissue strategies in addressing the complexities of neuronal aging. ### Competing Interest Statement The authors have declared no competing interest.