Explore the Optimal Treatment Regimen Across Combinations of Variate Protein Sources and Exercise Modalities and Its...

Background/Objectives: Aging is closely associated with sarcopenia, which has a significant impact on muscle mass and its function. Protein supplementation (PS) brings benefits such as lean mass and strength gains during exercise training. This paper determined the optimal regimen among the composites of variate protein sources and training modalities for older individuals. Methods: We comprehensively searched the electronic databases, namely MEDLINE Complete, PEDro, the Cochrane Library, Google Scholar, EMBASE, and the China National Knowledge Infrastructure, from its inception until December 2025. We included randomized controlled trials (RCTs) that examined the effectiveness of any type of PS combined with one of three exercise types-resistance, aerobic, or multicomponent training-in untrained older adults. The main outcomes used to identify sarcopenia were assessed, including lean mass, handgrip and leg strength, and physical mobility measures. Network meta-analysis (NMA) was performed by a frequentist method using random-effects models. The estimated treatment effect was expressed as the standard mean difference (SMD) with a 95% confidence interval (CI). Any potential factor moderating the treatment effect was determined by the meta-regression analyses, including participant characteristics and methodological factors. Certainty of evidence (CoE) was assessed by the GRADE framework. Results: In total, we included 235 RCTs (20,980 participants) for analyses. A total of 10 protein sources (whey, soy, casein, milk, and the others) were identified, corresponding to 24 monotherapy and combined regimens of PS and exercise. Among the treatment arms, whey plus resistance training was ranked as the most effective treatment for muscle mass (large SMD, 1.29; CoE, moderate) and leg strength (large SMD, 1.16; CoE, moderate); additionally, whey plus multicomponent exercise training achieved the most promising effects on such sarcopenia-related physical indicators such as chair rise (large effect, SMD = 1.09; CoE: high), timed up and go (medium SMD, 0.70; CoE, high), and global mobility score (large SMD, 1.02; CoE, high). Conclusions: The treatment efficacy appears to be moderated by the participant's conditions, PS resource, and PS dose, particularly the outcome of muscle mass and strength. The present NMA results indicate that whey protein incorporated with resistance training is the optimal program to help combat sarcopenia in older adults.