Lien Evan C, Vu Ngoc, Westermark Anna M, Danai Laura V, Lau Allison N, Gültekin Yetiş, Kukurugya Matthew A, Bennett Bryson D, Vander Heiden Matthew G
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, Michigan, USA.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Aging Cell. 2025 Apr;24(4):e14462. doi: 10.1111/acel.14462. Epub 2024 Dec 27.
Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD, NADH, and the NAD/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD from NADH. These data suggest that NAD-generating lipid metabolism reactions may help to maintain the NAD/NADH ratio during healthy aging.
衰老伴随着多种分子变化，这些变化会导致与衰老相关的病理状况，如细胞损伤的积累和线粒体功能障碍。组织代谢也会随着年龄增长而发生变化，部分原因是线粒体在细胞代谢中起着核心作用。此外，据报道，辅因子NAD在衰老过程中会在多个组织中减少，它在糖酵解、三羧酸循环以及核苷酸、氨基酸和脂质的氧化合成等代谢途径中发挥着核心作用。为了进一步表征组织代谢如何随年龄变化，我们将[U-C]-葡萄糖静脉注射到年轻和年老的C57BL/6J、WSB/EiJ及多样性远交系小鼠体内，以追踪葡萄糖在血浆、肝脏、腓肠肌和脑组织中向下游代谢产物的转化情况。我们发现，在这些不同品系的小鼠健康衰老过程中，葡萄糖掺入中心碳代谢和氨基酸代谢的情况很显著。我们还观察到，在这些组织健康衰老的过程中，NAD、NADH的水平以及NAD/NADH比值均未发生变化。然而，衰老组织，尤其是脑组织，表现出脂肪酸和鞘脂代谢反应上调的迹象，这些反应可将NADH再生为NAD。这些数据表明，在健康衰老过程中，产生NAD的脂质代谢反应可能有助于维持NAD/NADH比值。
