表观遗传漂变是哺乳动物寿命的一个决定因素。
Epigenetic Drift Is a Determinant of Mammalian Lifespan.
作者信息
Mendelsohn Andrew R, Larrick James W
机构信息
1 Regenerative Sciences Institute , Sunnyvale, California.
2 Panorama Research Institute , Sunnyvale, California.
出版信息
Rejuvenation Res. 2017 Oct;20(5):430-436. doi: 10.1089/rej.2017.2024.
The epigenome, which controls cell identity and function, is not maintained with 100% fidelity in somatic animal cells. Errors in the maintenance of the epigenome lead to epigenetic drift, an important hallmark of aging. Numerous studies have described DNA methylation clocks that correlate epigenetic drift with increasing age. The question of how significant a role epigenetic drift plays in creating the phenotypes associated with aging remains open. A recent study describes a new DNA methylation clock that can be slowed by caloric restriction (CR) in a way that correlates with the degree of lifespan and healthspan extension conferred by CR, suggesting that epigenetic drift itself is a determinant of mammalian lifespan. Genetic transplantation using genomic editing of DNA methylation homeostatic genes from long-lived to short-lived species is one way to potentially demonstrate a causative role for DNA methylation. Whether the DNA methylation clock be reset to youthful state, eliminating the effects of epigenetic drift without requiring a pluripotent cell intermediate is a critical question with profound implications for the development of aging therapeutics. Methods that transiently erase the DNA methylation pattern of somatic cells may be developed that reset this aging hallmark with potentially profound effects on lifespan, if DNA methylation-based epigenetic drift really plays a primary role in aging.
控制细胞特性和功能的表观基因组在体细胞中并非以100%的保真度维持。表观基因组维持过程中的错误会导致表观遗传漂变,这是衰老的一个重要标志。许多研究描述了将表观遗传漂变与年龄增长相关联的DNA甲基化时钟。表观遗传漂变在产生与衰老相关的表型中所起的作用有多大,这个问题仍然没有答案。最近的一项研究描述了一种新的DNA甲基化时钟,热量限制(CR)可以使其变慢,其方式与CR赋予的寿命延长和健康寿命延长程度相关,这表明表观遗传漂变本身是哺乳动物寿命的一个决定因素。使用基因组编辑技术将长寿物种的DNA甲基化稳态基因移植到短寿物种中,是一种潜在地证明DNA甲基化具有因果作用的方法。DNA甲基化时钟是否能重置为年轻状态,在不需要多能细胞中间体的情况下消除表观遗传漂变的影响,这是一个关键问题,对衰老治疗学的发展具有深远意义。如果基于DNA甲基化的表观遗传漂变在衰老中真的起主要作用,那么可能会开发出暂时消除体细胞DNA甲基化模式的方法,这种方法可以重置这一衰老标志,对寿命产生潜在的深远影响。