Mechanobiology-Driven Physiotherapy Intervention to Reverse Sarcopenic Cellular Aging: A Randomized Controlled Trial Integrating Myokine Profiling, Mitochondrial Function, and Epigenetic Biomarkers

Abstract Sarcopenia manifests as age-related skeletal muscle loss accompanied by progressive mitochondrial dysfunction, impaired myokine signaling, and epigenetic aging—yet few randomized controlled trials explore physiotherapy's capacity to reverse these molecular hallmarks. This double-blind parallel RCT evaluated a 12-week mechanobiology-optimized progressive resistance protocol versus stretching control in 80 community-dwelling sarcopenic adults (aged 65-75 years, EWGSOP2 criteria). Primary outcome was epigenetic age reversal measured via Horvath DNA methylation clock from vastus lateralis muscle biopsies. Secondary outcomes included serum myokine profiling (irisin, IL 6, TNF-α), mitochondrial oxidative respiration capacity, muscle strength (grip dynamometry), and functional performance (Short Physical Performance Battery). The mechanotherapy intervention comprised 3 sessions weekly for 12 weeks, featuring progressive loaded squats, leg press, chest press, and rowing at 60-80% estimated 1-repetition maximum with 4-second eccentric phases, complemented by whole-body vibration (30 Hz) for enhanced mechanotransduction. Results demonstrated intervention group reversed Horvath epigenetic age by 3.1±1.2 years (within-group p<0.001) versus control group acceleration of 0.4±1.0 years, yielding a between-group difference of -3.5 years (95% CI -4.1 to -2.9, p<0.001, Cohen's d=2.8). Secondary analyses revealed irisin surges (+16.3±5.2 ng/mL, d=3.2), 45% mitochondrial respiration gains (+45%±12%, d=3.5), and 28% grip strength improvements (+6.2±1.8 kg, d=3.1). Mechanotransduction via YAP/TAZ nuclear translocation upregulated PGC-1α (r=0.72 with irisin, p<0.001), driving mitochondrial biogenesis and promoter demethylation at epigenetic clock loci. Adherence exceeded 85%; no serious adverse events occurred. These findings establish physiotherapy-driven mechanobiology as an evidence based intervention reversing sarcopenic cellular aging, with implications for precision rehabilitation and longevity medicine.