The age-dependency of cognitive decline is well-known in humans, however the mechanisms by which nervous system dysfunction is triggered during aging are poorly understood. Previous studies have reported age-related morphological changes of C. elegans neurons (including by Pan et al, 2011; Tank et al, 2011; Toth et al, 2012). We have expanded this analysis with a systematic survey of age-related neuronal changes in wild-type animals and find that neuron-type specific structural alterations occur across the entire nervous system during normal aging. Furthermore, our neuroanatomical analysis of long-lived mutants reveals that neuronal morphological alterations can be robustly delayed in some long-lived mutants, but not all, indicating that delayed age-related neuronal change is not always coupled with lifespan extension, consistent with findings on healthspan analysis (Bansal et al, 2015). We are dissecting the molecular pathways responsible for delaying age-related neuronal alterations in long-lived mutants and their interplay with neuronal maintenance molecules. One of these, SAX-7, is homologous to the L1CAM family of cell adhesion molecules in mammals, where it functions to preserve cognitive abilities in adults. We find that the loss or gain of function of
sax-7 affects neuronal structures in distinct ways that inform us on the process of neuronal aging. Our findings indicate that the interaction between molecular mechanisms dedicated to the lifelong maintenance of neuronal architecture and lifespan determination are key to age-related neuronal change. Given the conservation between the human and C. elegans genomes, and in neuronal processes, the genes that protect from or promote neuronal decline in C. elegans will advance our knowledge of the principles underlying neuronal maintenance and aging and may provide insights into age-related neurodegenerative diseases.