Background/objectives: this study evaluated the differential effects of two distinct dietary nucleotide supplements, combined with spontaneous physical activity, on neuromuscular, cognitive, and metabolic adaptations in older adults.

Methods: Sixty-nine physically independent older adults (aged 60-75 years) were randomly assigned to three groups: (1) a yeast nucleotides formulation (YN) standardized in a high content of free nucleotides (>40%) rich in all macro and micro nutrients naturally occurring in yeast cell (amino acids, minerals and B-group vitamin); (2) a neuro-based formulation (NF) consisting of a blend of monophosphate nucleotides 5'; or (3) a placebo. Participants maintained their spontaneous physical activities without structured exercise during a 10-week intervention. Assessments included physical function, cognitive performance, body composition, quality of life, and serum biomarkers of oxidative stress, inflammation, and neurogenesis.

Results: Both nucleotide-supplemented groups demonstrated significant improvements compared to placebo in physical performance (p ≤ 0.045), cognitive function (Trail Making Test B [TMT-B]: p ≤ 0.012), oxidative stress biomarkers (p ≤ 0.048), inflammatory cytokines (p ≤ 0.023), and quality-of-life parameters (p ≤ 0.047). Body composition remained stable in supplemented groups, whereas placebo increased fat mass (5.04%) and decreased muscle mass (-2.18%).

Conclusions: Dietary nucleotide supplementation enhances the benefits of spontaneous physical activity across all measured variables in older adults, highlighting nucleotides as promising nutritional support for healthy aging. YN exhibited a trend toward greater inflammatory modulation, whereas NF showed a tendency toward enhanced neurotrophic effects and functional improvements, with a statistically significant improvement in the Timed Up and Go Test (p = 0.014). These findings underscore the potential for tailored nucleotide-based interventions to optimize distinct physiological domains in aging populations.