Reduced expression of MYC increases longevity and enhances healthspan.
Reduced expression of MYC increases longevity and enhances healthspan.
复制标题
DOI：
10.1016/j.cell.2014.12.016
复制
发表时间：
2015-01-29
期刊：
影响因子：
64.5
通讯作者：
Sedivy JM
中科院分区：
文献类型：
--
作者：
Hofmann JW;Zhao X;De Cecco M;Peterson AL;Pagliaroli L;Manivannan J;Hubbard GB;Ikeno Y;Zhang Y;Feng B;Li X;Serre T;Qi W;Van Remmen H;Miller RA;Bath KG;de Cabo R;Xu H;Neretti N;Sedivy JM
MYC是一种高度多效性的转录因子，其失调促进癌症。相比之下，我们发现Myc单倍不足（Myc+/−）小鼠的寿命延长。它们对几种与年龄相关的病理学表现出抵抗力，包括骨质疏松症、心脏纤维化和免疫衰老。他们似乎也更活跃，代谢率更高，脂质代谢更健康。转录组学分析揭示了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剂的祖先作用反映在减少的蛋白质翻译中，这与寿命呈负相关。我们还观察到营养和能量感应途径的变化，包括血清IGF-1降低，AMPK活性增加，AKT，TOR和S6 K活性降低。与其他长寿模型的观察结果相反，Myc+/−小鼠在压力管理途径方面没有表现出改善。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显着影响。
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.