Development of a Multidomain Neuromuscular Aging Clock Integrating Clinical Neurosensory Dysfunction with Molecular Biomarkers

Background Neuromuscular aging involves neurosensory deterioration and molecular pathway alterations, yet metrics rarely integrate clinical dysfunction with biomarkers. Aims We developed a multidomain Neuromuscular Aging Clock (NAC) to quantify lower-limb neuromuscular biological aging integrating clinical neurosensory impairment with molecular neurobiological alterations. Methods 108 symptomatic adults and 108 age- and sex-matched controls were enrolled. Clinical dysfunction was assessed using the Composite Neuromuscular Dysfunction Index (CNDI), comprising nociceptive, neuropathic, thermal, and neurogenic domains. Molecular alterations were evaluated using the Composite Biological Neurofunctional Index (CBNI), incorporating neuroinflammation, muscle damage, oxidative stress, neurotrophic, and neuroglial biomarkers. Biomarkers were standardized using effect-size weighting. ROC analysis and meta-analytic synthesis evaluated discrimination. A Biological Age Index was calculated as a weighted sum of normalized CNDI and CBNI. Results Integrated indices discriminated between groups (p < 0.0001). Meta-analysis showed large pooled effects. The NAC estimated a mean biological age of 61.3 years in symptomatic participants versus 51.0 years chronological age, indicating ~ 10.3 years of age acceleration. Conclusions The NAC integrates clinical neurosensory dysfunction with molecular neurobiological alterations to quantify biological aging, enabling early detection of accelerated aging and risk stratification.