Metabolic adaptations occur with aging but the significance and causal roles of such changes are only partially known. In Drosophila, we find that skeletal muscle aging is paradoxically characterized by increased readouts of glycolysis (lactate, NADH/NAD+) but reduced expression of most glycolytic enzymes. This conundrum is explained by lactate dehydrogenase (LDH), an enzyme necessary for anaerobic glycolysis and whose expression increases with aging. Experimental Ldh overexpression in skeletal muscle of young flies increases glycolysis and shortens life span, suggesting that age-related increases in muscle LDH contribute to mortality. Similar results are also found with overexpression of other glycolytic enzymes (Pfrx/PFKFB, Pgi/GPI). Conversely, hypomorphic mutations in Ldh extend life span, whereas reduction in PFK, Pglym78/PGAM, Pgi/GPI, and Ald/ALDO levels shorten life span to various degrees, indicating that glycolysis needs to be tightly controlled for optimal aging. Altogether, these findings indicate a role for muscle LDH and glycolysis in aging.

中文翻译：

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骨骼肌中乳酸脱氢酶活性与年龄相关的增加会缩短果蝇的寿命

代谢适应随着衰老而发生，但这种变化的重要性和因果作用仅部分为人所知。在果蝇中，我们发现骨骼肌衰老的矛盾特征是糖酵解（乳酸、NADH/NAD+）读数增加，但大多数糖酵解酶的表达减少。这个难题可以通过乳酸脱氢酶 (LDH) 来解释，LDH 是无氧糖酵解所必需的酶，其表达随着年龄的增长而增加。幼果蝇骨骼肌中 Ldh 的实验性过度表达会增加糖酵解并缩短寿命，这表明肌肉 LDH 与年龄相关的增加会导致死亡率。其他糖酵解酶（Pfrx/PFKFB、Pgi/GPI）的过度表达也发现了类似的结果。相反，Ldh 的亚等位突变可延长寿命，而 PFK、Pglym78/PGAM、Pgi/GPI 的减少、Ald/ALDO 水平会不同程度地缩短寿命，这表明需要严格控制糖酵解才能实现最佳衰老。总而言之，这些发现表明肌肉 LDH 和糖酵解在衰老中发挥着作用。