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核糖体 DNA 携带着进化上保守的生物衰老时钟。

Ribosomal DNA harbors an evolutionarily conserved clock of biological aging.

机构信息

Department of Environmental Health, Program in Molecular and Integrative Physiological Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.

Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

出版信息

Genome Res. 2019 Mar;29(3):325-333. doi: 10.1101/gr.241745.118. Epub 2019 Feb 14.

Abstract

The ribosomal DNA (rDNA) is the most evolutionarily conserved segment of the genome and gives origin to the nucleolus, an energy intensive nuclear organelle and major hub influencing myriad molecular processes from cellular metabolism to epigenetic states of the genome. The rDNA/nucleolus has been directly and mechanistically implicated in aging and longevity in organisms as diverse as yeasts, , and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity. Here, we introduce an age clock built exclusively with CpG methylation within the rDNA. The ribosomal clock is sufficient to accurately estimate individual age within species, is responsive to genetic and environmental interventions that modulate life-span, and operates across species as distant as humans, mice, and dogs. Further analyses revealed a significant excess of age-associated hypermethylation in the rDNA relative to other segments of the genome, and which forms the basis of the rDNA clock. Our observations identified an evolutionarily conserved marker of aging that is easily ascertained, grounded on nucleolar biology, and could serve as a universal marker to gauge individual age and response to interventions in humans as well as laboratory and wild organisms across a wide diversity of species.

摘要

核糖体 DNA(rDNA)是基因组中最具进化保守性的片段,它起源于核仁,这是一个能量密集型的核细胞器,也是影响从细胞代谢到基因组表观遗传状态等众多分子过程的主要中心。rDNA/核仁直接并在机制上与酵母、 和人类等各种生物的衰老和长寿有关。rDNA 也是 DNA 甲基化的重要靶点,它可以沉默多余的 rDNA 单位并调节核仁活性。在这里,我们引入了一个仅由 rDNA 内的 CpG 甲基化构建的年龄时钟。核糖体时钟足以在物种内准确估计个体年龄,对调节寿命的遗传和环境干预有反应,并且在人类、老鼠和狗等相距甚远的物种中都能发挥作用。进一步的分析显示,rDNA 中与年龄相关的过度甲基化明显多于基因组的其他部分,这构成了 rDNA 时钟的基础。我们的观察结果确定了一种进化上保守的衰老标志物,这种标志物易于确定,基于核仁生物学,可以作为一种通用标志物,用于衡量人类以及实验室和野生生物个体的年龄以及对各种物种的干预的反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d947/6396418/acf6ecf74895/325f01.jpg

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