Aging promotes left ventricular hypertrophic remodeling and diastolic dysfunction, yet interventions that preserve cardiac function when initiated late in life remain limited. Butyrate, a gut microbiome derived short chain fatty acid, can act as both a metabolic substrate and an epigenetic modulator, but whether long term supplementation improves cardiac resilience in advanced age and through which multicellular programs is unclear. Here we treated male C57BL/6J mice with sodium butyrate beginning at 18 months of age and maintained treatment to 28 months. Compared with age matched controls, NaBu treated aged mice exhibited reduced left ventricular mass and improved cardiac diastolic function. Left ventricular bulk proteomics revealed a coordinated aging signature characterized by increased extracellular remodeling and innate immune/complement/hemostasis pathways and decreased metabolic and proteostasis networks; NaBu partially opposed age associated proteomic shifts and identified a subset of proteins that reversed direction between aging and NaBu axes. Single nucleus multiome profiling further resolved cellular and regulatory programs associated with aging and NaBu response. Aging induced extensive chromatin remodeling with the strongest coupled RNA and ATAC changes in cardiomyocytes. In aged hearts, NaBu was associated with a consistent reduction of endothelial IFN and MHCI antigen presentation and adhesion programs across endothelial subtypes, with concordant decreases in both RNA and chromatin accessibility/gene activity at key loci, consistent with reduced endothelial inflammatory priming. Together, physiological, proteomic, and multiome data support long term NaBu as a late life intervention that attenuates age-associated cardiac remodeling and reshapes multicellular molecular programs in the aged heart.
Snyder, M., Tong, M.
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