Clonal hematopoiesis and accelerated metabolic dysfunction in obesity

摘要 随着时间的推移，体细胞DNA突变的积累是许多组织衰老的标志。然而， 体细胞突变在癌症以外的年龄相关疾病中的因果作用是一个有争议的问题。 在代谢性疾病的背景下仍未被探索。人类大型外显子组测序研究进展 已经表明，衰老不可避免地与老年人的体细胞突变频率增加有关 造血系统，这为突变细胞提供了竞争生长优势，从而使其 克隆性扩增(克隆性造血)。出乎意料的是，这些体细胞突变与 较高的心脏代谢性疾病发生率，表明躯体疾病之间存在以前不为人知的联系 骨髓来源细胞的突变和这些疾病过程。但是，是否有一个 这些体细胞突变和代谢功能障碍之间的因果关系尚不清楚 潜在的潜在机制尚不清楚，这是拟议研究的科学前提。

ABSTRACT The accumulation of somatic DNA mutations over time is a hallmark of aging in many tissues. However, the causal role of somatic mutations in age-associated disorders other than cancer is a matter of debate, and remains unexplored in the setting of metabolic disease. Recent large exome sequencing studies in humans have shown that aging is inevitably associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive growth advantage to the mutant cell and thus allow its clonal expansion (clonal hematopoiesis). Unexpectedly, these somatic mutations were associated with a higher rates of cardio-metabolic disease, suggesting a previously unrecognized link between somatic mutations in bone marrow-derived cells and these disease processes. However, whether there is a causal connection between these somatic mutations and metabolic dysfunction remains unclear and the potential underlying mechanisms are unknown, and this is the scientific premise of the proposed research.