Background/Objectives: Aging is characterized by progressive physiological and metabolic decline. Aerobic exercise mitigates age-related impairments, and nicotinamide mononucleotide (NMN), a precursor in the NAD+ salvage pathway, has emerged as a nutritional intervention to promote healthy aging. This study investigated whether NMN supplementation combined with aerobic exercise provides synergistic benefits on physical performance and metabolic regulation in aged mice. Methods: Forty male C57BL/6J mice, including eight young (8 weeks) and thirty-two aged (85 weeks) mice, were randomly assigned to five groups: young sedentary (YS), aged sedentary (AS), aged with exercise (AE), aged with NMN (ASNMN; 300 mg/kg/day), and aged with combined NMN and exercise (AENMN). Interventions lasted six weeks. Assessments included grip strength, muscle endurance, aerobic capacity, oral glucose tolerance test (OGTT), and indirect calorimetry, followed by biochemical and molecular analyses of NAMPT and SirT1 expression. Results: The AENMN group demonstrated significant improvements in maximal strength and aerobic endurance compared with the AS group (p < 0.05). Both NMN and exercise interventions increased blood NAMPT concentrations, with the highest levels observed in the AENMN group (p < 0.05). SirT1 expression was elevated in the ASNMN and AENMN groups relative to YS (p < 0.05). Glucose tolerance improved in the ASNMN and AENMN groups (p < 0.05). Enhanced energy metabolism in the AENMN group was indicated by increased oxygen consumption, elevated energy expenditure, and reduced respiratory quotient. Conclusions: NMN supplementation, particularly when combined with aerobic exercise, effectively improved aerobic performance, glucose regulation, and systemic energy metabolism in aged mice. These findings suggest that NMN, in synergy with exercise, may serve as a promising nutritional strategy to counteract age-associated metabolic and functional decline.
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