Aging clocks delineate neuron types vulnerable or resilient to neurodegeneration and identify neuroprotective interventions.

Abstract

Different neuron types show distinct susceptibility to age-dependent degeneration, yet the underlying mechanisms are poorly understood. Here we applied aging clocks to single neuron types in Caenorhabditis elegans and found that distinct neurons differ in their biological age. Ciliated sensory neurons with high neuropeptide and protein biosynthesis gene expression show accelerated aging and degeneration, correlating with loss of function, which could be prevented by pharmacological inhibition of translation. We show that the C. elegans neuronal aging transcriptomes correlate with human brain aging patterns and anticorrelate with geroprotective interventions. We performed an in silico drug screen to identify potentially neuroprotective small molecules. We show that the natural occurring plant metabolite syringic acid and the piperazine derivative vanoxerine delay neuronal degeneration, and propose these compounds as neuroprotective interventions. Furthermore, we identify neurotoxins that accelerate neurodegeneration, indicating that distinguishing aging trajectories between neuron types can inform on protective interventions as well as risk factors.