Neuron-type specific aging-rate reveals age decelerating interventions preventing neurodegeneration

Abstract Different types of neurons show distinct susceptibility to age-dependent functional decline and degeneration and are linked to different types of neurodegenerative disorders. The underlying reasons for different aging trajectories of distinct neuron types are poorly understood. Here, we employ aging clocks to assess whether distinct neurons differ in their biological age trajectory in C. elegans where the identity of each single neuron is known. We find that specifically ciliated sensory neurons with high neuropeptide expression show the most rapidly progressing biological age. The more rapidly aging neurons show a reduction of mitochondrial respiration and elevated protein translation gene expression. Reducing protein translation with cycloheximide effectively protected fast aging neurons. We show that the C. elegans neuronal aging pattern are highly correlated with human brain aging and contrasted by geroprotective interventions. We performed an in silico drug screen and identified known and novel neuroprotective small molecule compounds. We show that the natural occurring plant metabolite syringic acid and the piperazine derivative vanoxerine delay neuronal degeneration and propose that they could serve as neuroprotective interventions. We also identify neurotoxins that accelerate neurodegeneration indicating that this approach could reveal interventions as well as risk factors for neuronal aging.