In aged mice, strength, coordination, and neuromuscular excitability declined while cortical output to muscle increased, with layer V pyramidal neurons of the primary motor cortex showing hyperexcitability, altered synaptic input, and shifts in excitability-related gene expression. Across 250 cortical–neuromuscular pairwise comparisons, firing frequency of these neurons was the strongest correlate of neuromuscular dysfunction, statistically accounting for 75% of the age effect. The work positions the motor cortex, not only muscle mass or the neuromuscular junction, as a candidate site of age-related weakness.
Key Points
- Aged mice showed weakness despite increased cortical motor output to muscle
- Layer V pyramidal neuron firing explained 75% of age effect
- Cortical hyperexcitability correlated with worse strength and coordination outcomes
Longevity Analysis
Grip strength and gait speed predict disability and mortality more reliably than muscle mass alone, and this work offers a mechanistic reason why: the command signal itself degrades before the tissue does. Interpreting late-life weakness as a purely muscular problem risks directing effort toward tissue building while the upstream driver — dysregulated excitability in the neural circuits that generate movement — remains unaddressed. Interventions that maintain cortical inhibitory balance and motor circuit fidelity, including skilled movement practice, sleep-dependent consolidation, and control of chronic inflammatory and metabolic load on neural tissue, become as relevant to preserving strength as resistance training itself.
Original published by Wiley Aging Cell, by Jose A. Viteri, Nathan R. Kerr, Fereshteh B. Darvishi, Anna Roshani Dashtmian, Charles D. Brennan, Sindhuja N. Ayyagari, Peter J. Moore, Meifang Wang, Harper Snyder, Baocong Yu, Joseph M. Santin, W. David Arnold .