Calico Life Sciences LLC, South San Francisco, CA 94080.
Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2119593119. doi: 10.1073/pnas.2119593119. Epub 2022 Apr 8.
The complex processes and interactions that regulate aging and determine lifespan are not fully defined for any organism. Here, taking advantage of recent technological advances in studying aging in budding yeast, we discovered a previously unappreciated relationship between the number of copies of the ribosomal RNA gene present in its chromosomal array and replicative lifespan (RLS). Specifically, the chromosomal ribosomal DNA (rDNA) copy number (rDNA CN) positively correlated with RLS and this interaction explained over 70% of variability in RLS among a series of wild-type strains. In strains with low rDNA CN, SIR2 expression was attenuated and extrachromosomal rDNA circle (ERC) accumulation was increased, leading to shorter lifespan. Suppressing ERC formation by deletion of FOB1 eliminated the relationship between rDNA CN and RLS. These data suggest that previously identified rDNA CN regulatory mechanisms limit lifespan. Importantly, the RLSs of reported lifespan-enhancing mutations were significantly impacted by rDNA CN, suggesting that changes in rDNA CN might explain the magnitude of some of those reported effects. We propose that because rDNA CN is modulated by environmental, genetic, and stochastic factors, considering rDNA CN is a prerequisite for accurate interpretation of lifespan data.
调控衰老和寿命的复杂过程和相互作用在任何生物体中都没有被完全定义。在这里，我们利用最近在研究芽殖酵母衰老方面的技术进展，发现了一个以前未被重视的现象，即在其染色体数组中存在的核糖体 RNA 基因的拷贝数与复制寿命（RLS）之间存在着关系。具体来说，染色体核糖体 DNA（rDNA）的拷贝数（rDNA CN）与 RLS 呈正相关，并且这种相互作用解释了一系列野生型菌株之间 RLS 变异性的 70%以上。在 rDNA CN 较低的菌株中，SIR2 的表达减弱，额外的染色体 rDNA 环（ERC）积累增加，导致寿命缩短。通过删除 FOB1 来抑制 ERC 的形成，消除了 rDNA CN 与 RLS 之间的关系。这些数据表明，以前确定的 rDNA CN 调节机制限制了寿命。重要的是，报告的延长寿命的突变的 RLS 受到 rDNA CN 的显著影响，这表明 rDNA CN 的变化可能解释了一些报道的效应的程度。我们提出，由于 rDNA CN 受到环境、遗传和随机因素的调节，因此考虑 rDNA CN 是准确解释寿命数据的前提。
