Impact of a high-protein diet with and without strength training over 17 weeks on the plasma metabolome in older adults

Background: Age-associated loss of skeletal muscle mass impairs metabolic health, increases disease risk and diminishes response to therapeutic interventions. Optimising dietary protein intake combined with resistance training has been proposed as an effective strategy to preserve muscle mass in older adults. While the clinical benefits of such lifestyle interventions are known, the long-term metabolic safety and precise systemic changes at the metabolome level in older adults remain uncharacterised. Methods: In the NutriAging Protein study, 136 men and women aged 65–85 years were randomised into three groups: control, recommended-protein and high-protein groups. Participants underwent a 17-week intervention, combining a 6-week dietary intervention followed by 8 weeks of supervised resistance training in the high-protein and recommended-protein groups. Plasma samples were collected at baseline, Week 8 and Week 17. An untargeted metabolomics approach based on ultra-high-performance liquid chromatography–mass spectrometry was employed to characterise systemic metabolic alterations across interventions. Results: The high-protein group increased their daily protein intake to 1.6 g/kg body weight and exhibited significantly increased concentrations of two metabolites and reduced concentrations of 98 metabolites compared to baseline. Most metabolite shifts occurred during the dietary intervention phase, with minimal additional changes after resistance training. Affected metabolites belonged primarily to lipid subclasses, energy and amino acid metabolism intermediates, and pathways linked to heme degradation and the urea cycle. Conclusion: A high-protein diet, alone or combined with resistance training, induces modest but measurable metabolic shifts without disrupting global metabolic homeostasis. These findings suggest that older adults can adapt to elevated protein intake while maintaining metabolic stability, supporting the metabolic safety of a high-protein diet in combination with resistance exercise. https://clinicaltrials.gov