Hofmann Jeffrey W, Zhao Xiaoai, De Cecco Marco, Peterson Abigail L, Pagliaroli Luca, Manivannan Jayameenakshi, Hubbard Gene B, Ikeno Yuji, Zhang Yongqing, Feng Bin, Li Xiaxi, Serre Thomas, Qi Wenbo, Van Remmen Holly, Miller Richard A, Bath Kevin G, de Cabo Rafael, Xu Haiyan, Neretti Nicola, Sedivy John M
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
Department of Cellular and Structural Biology, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Cell. 2015 Jan 29;160(3):477-88. doi: 10.1016/j.cell.2014.12.016. Epub 2015 Jan 22.
MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.
MYC是一种高度多效性的转录因子，其失调会促进癌症发生。相比之下，我们发现Myc单倍体不足（Myc(+/-)）的小鼠寿命延长。它们对几种与年龄相关的病理状况具有抵抗力，包括骨质疏松症、心脏纤维化和免疫衰老。它们似乎也更活跃，具有更高的代谢率和更健康的脂质代谢。转录组分析揭示了一个富含代谢和免疫过程的基因表达特征。MYC作为核糖体生物发生调节因子的原始作用体现在蛋白质翻译减少上，这与寿命呈负相关。我们还观察到营养和能量传感途径的变化，包括血清IGF-1降低、AMPK活性增加以及AKT、TOR和S6K活性降低。与其他长寿模型的观察结果不同，Myc(+/-)小鼠在应激管理途径方面没有改善。我们的研究结果表明，MYC活性对哺乳动物的寿命和健康寿命的多个方面有重大影响。
