Butyrate supplementation reshapes systemic metabolism and attenuates cardiac aging

Identifying interventions that improve health and cardiac function is important for extending healthspan. We show that supplementation with the SCFA butyrate beginning at 18 months (late life) extends survival in male and female mice and improves systemic metabolic and physical-performance measures. Treatment reduces adiposity and fasting glucose and attenuates age-associated cardiac hypertrophy, fibrosis, and systolic and diastolic dysfunction. Integrated plasma and myocardial metabolomics and lipidomics reveal compartment-dependent metabolic remodeling, while cardiac proteomics and full-length RNA sequencing identify coordinated changes in extracellular-matrix, RNA-processing, lipid-metabolism, and autophagy-associated programs. These molecular responses are accompanied by improved mitochondrial ultrastructural organization and respiratory function. Butyrate supplementation also enhanced cardiac autophagy and mitophagy, and its beneficial effects on LV hypertrophy and diastolic indices required ATG7. These findings demonstrate that butyrate supplementation initiated at an advanced age modifies systemic and cardiac aging phenotypes and implicate metabolic remodeling and mitochondrial quality control pathways as contributing to these benefits.