Faakye Anna, Harold Kylene M, Matsuzaki Satoshi, Pranay Atul, Mendez Garcia Maria F, Loveland Brooke L, Rigsby Sandra N, Peelor Frederick F, Eyster Craig, Miller Benjamin F, Griffin Timothy M, Kinter Michael, Chiao Ying Ann, Humphries Kenneth M
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13 th Street, Oklahoma City, OK, USA.
Department of Biochemistry and Molecular Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Geroscience. 2025 May 1. doi: 10.1007/s11357-025-01656-z.
Cardiac aging is associated with metabolic changes, including an increased reliance on glycolysis, and an increased susceptibility to cardiovascular diseases. This study explores the relationship between enhanced cardiac glycolysis and aging using the Glyco mouse model, characterized by constitutively elevated glycolysis. We compared cardiac function, metabolism, mitochondrial performance, and hallmarks of aging between aged (21 and 24 months) Glyco and wild-type (WT) mice across sexes. Our findings reveal modest reductions in cardiac function in aged Glyco mice compared to WT mice, with sex-specific differences in heart size and collagen concentration. Female Glyco hearts exhibited hypertrophy without fibrosis, while males showed elevated collagen levels. Whole-body metabolic assessments revealed similar energy expenditure and respiratory patterns across genotypes, with females displaying less circadian-associated variation in metabolism. Mitochondrial analyses showed that aged Glyco hearts maintained metabolic adaptations favoring glycolysis but did not exhibit significant bioenergetic dysfunction or oxidative stress. Pyruvate dehydrogenase activity, initially elevated in younger Glyco hearts, normalized to WT levels with age. Proteomic and metabolomic analyses highlighted distinct profiles between genotypes, with Glyco hearts exhibiting increased glycolytic enzyme levels and reduced abundance of fatty acid oxidation proteins. Despite these differences, indicators of oxidative stress, proteostasis, and cellular senescence were comparable between genotypes, suggesting no acceleration of aging-related dysfunction. This study demonstrates that increased cardiac glycolysis alone does not suffice to drive accelerated cardiac aging. Instead, metabolic and functional changes in aged Glyco hearts reflect adaptations rather than pathological declines, providing insights into potential metabolic targets for interventions against cardiac aging.
心脏衰老与代谢变化相关，包括对糖酵解的依赖性增加以及对心血管疾病的易感性增加。本研究使用糖酵解小鼠模型（其特征为组成性糖酵解升高）探索增强的心脏糖酵解与衰老之间的关系。我们比较了不同性别的老年（21和24个月）糖酵解小鼠和野生型（WT）小鼠之间的心脏功能、代谢、线粒体性能和衰老特征。我们的研究结果显示，与WT小鼠相比，老年糖酵解小鼠的心脏功能有适度降低，在心脏大小和胶原蛋白浓度方面存在性别特异性差异。雌性糖酵解小鼠的心脏表现为肥大但无纤维化，而雄性小鼠的胶原蛋白水平升高。全身代谢评估显示，不同基因型之间的能量消耗和呼吸模式相似，雌性小鼠在代谢方面的昼夜节律相关变化较小。线粒体分析表明，老年糖酵解小鼠的心脏维持了有利于糖酵解的代谢适应，但未表现出明显的生物能量功能障碍或氧化应激。丙酮酸脱氢酶活性在年轻的糖酵解小鼠心脏中最初升高，但随着年龄增长恢复到WT水平。蛋白质组学和代谢组学分析突出了不同基因型之间的不同特征，糖酵解小鼠的心脏表现出糖酵解酶水平升高和脂肪酸氧化蛋白丰度降低。尽管存在这些差异，但不同基因型之间的氧化应激、蛋白质稳态和细胞衰老指标相当，表明与衰老相关的功能障碍没有加速。这项研究表明，仅心脏糖酵解增加不足以驱动心脏衰老加速。相反，老年糖酵解小鼠心脏的代谢和功能变化反映了适应性变化而非病理性衰退，为针对心脏衰老的干预措施提供了潜在的代谢靶点。
