Neural mechanisms of age-related weakness

This work investigates neural contributions to age-related muscle weakness by examining motor cortical excitability and voluntary activation in older adults. Recognizing that loss of muscle mass alone does not fully explain declines in strength with aging, the study tests the hypothesis that weaker seniors exhibit impairments in the nervous system’s ability to activate muscle and increased GABAergic inhibition within the motor cortex. The authors compared young adults (N = 46; mean age ≈21 years) and seniors (N = 42; mean age ≈71 years) and performed a secondary analysis contrasting stronger seniors (top two tertiles for strength relative to body weight) with weaker seniors (bottom tertile). Strength was quantified via wrist flexion tasks and voluntary activation (VA) was assessed by comparing voluntary forces to forces evoked electrically, using the interpolated twitch technique. Transcranial magnetic stimulation (TMS) provided measures of corticospinal and intracortical excitability. Single-pulse TMS elicited motor-evoked potential (MEP) amplitudes and silent period durations during isometric contractions at 15% and 30% of maximum strength, while paired-pulse TMS evaluated intracortical facilitation (ICF) and short-interval (SICI) and long-interval intracortical inhibition (LICI).

The principal and novel findings reveal that weaker seniors demonstrate marked neural deficits compared with stronger seniors and young adults. Specifically, weaker seniors showed an approximate 20% deficit in voluntary activation, indicating a reduced capacity of the nervous system to fully drive muscle during maximal effort. During the 30% contraction task, weaker seniors exhibited about 20% smaller MEP amplitudes, suggesting diminished corticospinal excitability under active conditions. At rest, weaker seniors displayed nearly twofold higher levels of LICI, implicating enhanced GABAergic inhibition mediated by GABA-B receptor mechanisms as a possible contributor to diminished motor cortical output. Collectively, these results support the interpretation that age-related weakness—often labeled dynapenia—is not solely attributable to loss of muscle mass but also involves central neural mechanisms, including reduced voluntary activation and increased intracortical inhibition.

The study highlights heterogeneity within the older population, demonstrating that weaker seniors possess distinct neurophysiological profiles compared with their stronger peers. Methodologically, the integration of electrical stimulation, interpolated twitch measures, and multiple TMS protocols provides a comprehensive assessment of neural activation capacity and intracortical inhibitory/excitatory balance. Clinically, identifying neural contributors to weakness emphasizes the potential for interventions targeting the central nervous system—such as neuromodulatory techniques, pharmacologic modulation of inhibitory neurotransmission, or targeted neurorehabilitation strategies—to complement traditional muscle-focused therapies. By delineating specific cortical mechanisms associated with weakness, this research informs future work aiming to restore motor function and reduce disability risk in older adults.