Neurodegeneration has increasingly been considered an important factor in the pathogenesis of sarcopenia or age-related loss of muscle mass and strength. Experiments were designed to investigate the fidelity of neuromuscular junction (NMJ) transmission across the lifespan in hindlimb muscles of male and female C57BL/6J mice (at 12, 20, 24, 27, and 29 months of age). Single-fiber electromyography recordings demonstrated abrupt onset of NMJ transmission failure at 27 months of age. Failed NMJ transmission was a later onset phenotype as compared with other assessments of motor unit numbers, muscle contractility, and frailty which showed alterations at 20 months of age. Ex vivo NMJ recordings demonstrated no reduction of endplate current amplitude in support of reduced muscle fiber excitability as the cause of failed NMJ transmission in aged mice. Improved understanding of age-related neurodegeneration will likely have important implications in designing novel therapeutic interventions specific for different stages of sarcopenia. Our findings suggest reduced muscle excitability may be a potential therapeutic target for improvement of physical function in older adults.