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Nat 70岁后,人快速衰老的原因 驱动突变衰老恶化癌变

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发表于 2022-6-10 11:40:22 | 显示全部楼层 |阅读模式
本帖最后由 邓文龙 于 2022-6-10 12:17 编辑

Natur俄:70岁后,人快速衰老的原因 驱动突变衰老恶化癌变

人类一生中造血的克隆动力学。 克隆性造血的纵向动力学和自然史。 65岁以下成年人体内的血细胞主要由2万~20万个干细胞提供,每个干细胞的贡献大致相等。而70岁以上的老年人体内均存在一组扩增造血的血液干细胞子集,只含有10-20个干细胞,但却负责生产多达一半的血细胞。在人一生中,这类高度活跃的干细胞的数量会逐渐增加,而这是由于一种罕见的、被称为“驱动突变”(driver mutations)的体细胞突变引起的。引发衰老、器官功能恶化和癌变等。

环球科学

2022/06/10

论文一
论文二
论文标题:Clonal dynamics of haematopoiesis across the human lifespan
作者:Emily Mitchell, Michael Spencer Chapman, Peter J. Campbell, et al.
期刊:Nature
发表时间:2022/06/01
数字识别码:10.1038/s41586-022-04786-y
摘要:Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4,5,6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000–200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30–60% of haematopoiesis was accounted for by 12–18 independent clones, each contributing 1–34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

所属学科:
遗传学
随着年龄渐长,人体各类组织内的体细胞都不可避免地会出现突变,积累的突变可能会导致细胞衰老、丧失功能等,但其如何导致70岁后人体器官的功能突然恶化还尚不清楚。6月1日,一项发表于《自然》的新研究指出,血液中某些干细胞累积的突变可能是导致老年人(70岁以上)的血液生产出现重大改变的原因。



研究人员分析了10位参与者(从幼儿到老年人不等)体内的骨髓造血过程,对共3579个血液干细胞进行了全基因组测序,确定了细胞中所有的体细胞突变。他们发现,65岁以下成年人体内的血细胞主要由2万~20万个干细胞提供,每个干细胞的贡献大致相等。而70岁以上的老年人体内均存在一组扩增造血的血液干细胞子集,只含有10-20个干细胞,但却负责生产多达一半的血细胞。在人一生中,这类高度活跃的干细胞的数量会逐渐增加,而这是由于一种罕见的、被称为“驱动突变”(driver mutations)的体细胞突变引起的。



在另一项发表于《自然》的研究中,研究人员发现不同的“驱动突变”会影响干细胞的生长速度,而生长更快的干细胞会取代生长慢的干细胞,负责生产更多的血细胞,但生长更快的代价是产生功能健全的血细胞的能力会受损。这种改变也导致人在70岁以后血细胞种群多样性急剧减少,从而引发衰老、器官功能恶化和癌变等问题。  

https://www.nature.com/articles/s41586-022-04786-y

https://www.nature.com/articles/s41586-022-04785-z

https://www.linkresearcher.com/t ... 6-b3d7-3869b744c43c



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