Nirmala Farida S, Lee Hyunjung, Cho Yejin, Um Min Young, Seo Hyo Deok, Jung Chang Hwa, Hahm Jeong-Hoon, Ahn Jiyun
Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, South Korea; Department of Food Biotechnology, Korea University of Science and Technology, Daejeon-si, South Korea.
Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, South Korea.
Redox Biol. 2025 Mar;80:103512. doi: 10.1016/j.redox.2025.103512. Epub 2025 Jan 27.
Sarcopenia, the age-related decline in muscle mass and function, is a significant contributor to increased frailty and mortality in the elderly. Currently, no FDA-approved treatment exists for sarcopenia. Here, we identified norharmane (NR), a β-carboline alkaloid, as a potential therapeutic agent for mitigating muscle aging. We aimed to determine the ability of NR to delay muscle aging in Caenorhabditis elegans (C. elegans), mouse, and muscle cells in mice and humans. NR treatment improved swimming ability and increased the maximum velocity in aged C. elegans. Transcriptomic analysis revealed that NR upregulated detoxification genes in C. elegans, including cytochrome P450, UGT, and GST enzymes. NR-induced benefits were dependent on the SKN-1/Nrf2 stress response pathway. In mammalian models, NR delayed cellular senescence in human skeletal muscle myoblasts and enhanced myogenesis in C2C12 cells and primary aged myoblasts. NR supplementation in aged mice prevented muscle loss, improved muscle function, and reduced markers of cellular senescence. We found that the p38 MAPK pathway mediated NR activation of Nrf2 by disrupting the Nrf2-Keap1 interaction. NR also improved oxygen consumption rates and promoted mitochondrial biogenesis. These findings suggest that NR is a promising candidate for preventing sarcopenia and improving muscle health.
肌肉减少症是与年龄相关的肌肉质量和功能下降，是导致老年人虚弱和死亡率增加的重要因素。目前，美国食品药品监督管理局（FDA）尚未批准用于治疗肌肉减少症的药物。在此，我们确定了一种β-咔啉生物碱去甲哈尔满（NR）是一种减轻肌肉衰老的潜在治疗剂。我们旨在确定NR在秀丽隐杆线虫、小鼠以及小鼠和人类肌肉细胞中延缓肌肉衰老的能力。NR治疗改善了衰老秀丽隐杆线虫的游泳能力并提高了其最大速度。转录组分析表明，NR上调了秀丽隐杆线虫中的解毒基因，包括细胞色素P450、尿苷二磷酸葡萄糖醛酸基转移酶（UGT）和谷胱甘肽S-转移酶（GST）等酶。NR诱导的益处依赖于SKN-1/Nrf2应激反应途径。在哺乳动物模型中，NR延缓了人类骨骼肌成肌细胞的细胞衰老，并增强了C2C12细胞和原代衰老成肌细胞的肌生成。给衰老小鼠补充NR可防止肌肉流失，改善肌肉功能，并减少细胞衰老标志物。我们发现p38丝裂原活化蛋白激酶（MAPK）途径通过破坏Nrf2- Kelch样环氧氯丙烷相关蛋白1（Keap1）相互作用介导了NR对Nrf2的激活。NR还提高了耗氧率并促进了线粒体生物发生。这些发现表明，NR是预防肌肉减少症和改善肌肉健康的有前途的候选物。
