Dietary Glutamine Supplementation Mitigates Age-Associated Cardiac Decline by Restricting H3K27me3

Epigenetic alterations are central drivers of cardiovascular aging, with histone modifications regulating gene expression through chromatin remodeling and changes in DNA accessibility. However, the mechanisms underlying these epigenetic shifts in the aging heart remain poorly defined. Here, we identify an age-associated accumulation of the repressive histone mark H3K27me3 in the myocardium of mice and humans, implicating this modification in myocardial aging. Elevated H3K27me3 was associated with impaired glutamine metabolism, driven by reduced expression of the amino acid transporter SLC1A5. Clinically, low circulating glutamine levels correlated with increased heart failure incidence, and genetic variants in SLC1A5 were linked to heightened cardiovascular disease risk. Mechanistically, elevated myocardial H3K27me3 suppressed cardiomyocyte autophagy and induced metabolic reprogramming, thereby promoting age-related myocardial dysfunction. Dietary glutamine supplementation in aged mice reduced H3K27me3 accumulation and improved myocardial function. Collectively, these findings identify a novel epigenetic mechanism underlying cardiac aging and highlight the glutamine–SLC1A5 axis as a potential therapeutic target for preserving myocardial function with age.