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.

表观遗传改变（epigenetic alterations）是心血管衰老的核心驱动因素，组蛋白修饰（histone modifications）通过染色质重塑（chromatin remodeling）与DNA可及性（DNA accessibility）变化调控基因表达。然而，衰老心脏中此类表观遗传变化的潜在机制仍未得到充分阐明。本研究鉴定出小鼠与人类心肌组织中随年龄积累的抑制性组蛋白修饰H3K27me3，证实该修饰参与心肌衰老过程。升高的H3K27me3水平与受损的谷氨酰胺代谢密切相关，该现象由氨基酸转运蛋白SLC1A5的表达下调所介导。临床研究显示，循环谷氨酰胺水平较低与心力衰竭发病率升高存在相关性，而SLC1A5的遗传变异与心血管疾病风险升高显著关联。机制层面，心肌组织中升高的H3K27me3会抑制心肌细胞自噬（cardiomyocyte autophagy）并诱导代谢重编程（metabolic reprogramming），进而促进年龄相关性心肌功能障碍。对老年小鼠实施膳食谷氨酰胺补充，可减少H3K27me3的积累并改善心肌功能。综上，本研究明确了心脏衰老背后的一种新型表观遗传机制，并揭示谷氨酰胺-SLC1A5轴可作为维持衰老过程中心肌功能的潜在治疗靶点。