Probiotic supplementation as a nutritional strategy for the prevention and management of sarcopenia in older adults.

Introduction: Sarcopenia, defined as the loss of skeletal muscle mass, strength, and functional capacity over time, poses a significant health burden among older adults. A growing body of evidence indicates that the gut microbiota contributes to inflammation and metabolic regulation, mitochondrial function, and anabolic signaling, thereby shaping the gut-muscle axis. Probiotic supplementation has gained traction as a nutritional approach for the regulation of microbiome-derived metabolites. The present study aims to assess the rationale for probiotic supplementation to prevent and manage sarcopenia in older individuals. Methods: Using data from NHANES (2011-2018; n = 3,500), UK Biobank (n = 5,000), and GMrepo (n = 800), we examined associations between probiotic exposure and muscle outcomes, inflammation, and microbiome diversity. C2C12 myotubes were used in vitro under probiotic-conditioned media (PCM). The interactions of short-chain fatty acids (SCFAs) with the regulatory proteins (mTOR, AMPK, NF-κB) were evaluated using molecular docking simulations. Random Forest and XGBoost models were used to predict sarcopenia risk using integrated multimodal features, with a 70% training and 30% validation split. Results: Probiotic users exhibited greater handgrip strength (UK Biobank: 27.2 ± 4.8 kg vs. 25.1 ± 5.2 kg), higher fat-free mass (57.4 ± 10.6 kg vs. 56.2 ± 11.0 kg), and lower inflammatory burden compared to non-users. PCM increased fusion index (85.6 ± 2.3% vs. 78.9 ± 3.2%, p < 0.01), myotube diameter (45.2 ± 6.3 μm vs. 40.1 ± 5.7 μm, p < 0.05), and MyoD (2.1-fold), Myogenin (1.8-fold), and MyHC (2.2-fold). NF-κB and TNF-α were decreased (~0.60-fold and 0.65-fold, respectively), and PGC-1α was increased (1.9-fold). Butyrate docking revealed high binding affinity for AMPK (-6.9 kcal/mol), mTOR (-6.4 kcal/mol), and NF-κB (-6.0 kcal/mol). The performance metrics achieved highly in XGBoost with 88% accuracy. Discussion: This comprehensive framework positions probiotics as a precision nutrition intervention for sarcopenia prevention, targeting muscle-sparing effects through microbiome modulation that stimulates coordinated immunometabolic and anabolic actions, with AI-enhanced, individualized risk prediction for healthy aging.