BioCircuits Institute, University of California, San Diego, La Jolla, San Diego, CA 92093, USA.
Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, San Diego, CA 92093, USA.
Cell Syst. 2019 Mar 27;8(3):242-253.e3. doi: 10.1016/j.cels.2019.02.002. Epub 2019 Mar 6.
Although genetic mutations that alter organisms' average lifespans have been identified in aging research, our understanding of the dynamic changes during aging remains limited. Here, we integrate single-cell imaging, microfluidics, and computational modeling to investigate phenotypic divergence and cellular heterogeneity during replicative aging of single S. cerevisiae cells. Specifically, we find that isogenic cells diverge early in life toward one of two aging paths, which are characterized by distinct age-associated phenotypes. We captured the dynamics of single cells along the paths with a stochastic discrete-state model, which accurately predicts both the measured heterogeneity and the lifespan of cells on each path within a cell population. Our analysis suggests that genetic and environmental factors influence both a cell's choice of paths and the kinetics of paths themselves. Given that these factors are highly conserved throughout eukaryotes, divergent aging might represent a general scheme in cellular aging of other organisms.
尽管在衰老研究中已经确定了改变生物体平均寿命的遗传突变，但我们对衰老过程中动态变化的理解仍然有限。在这里，我们整合了单细胞成像、微流控和计算建模，以研究单个酿酒酵母细胞复制衰老过程中的表型分歧和细胞异质性。具体来说，我们发现同基因细胞在生命早期就朝着两种衰老途径中的一种分化，这两种途径的特征是具有不同的与年龄相关的表型。我们使用随机离散状态模型来捕获沿这些途径的单个细胞的动态，该模型准确地预测了细胞群体中每个途径上细胞的异质性和寿命。我们的分析表明，遗传和环境因素既影响细胞对途径的选择，也影响途径本身的动力学。鉴于这些因素在真核生物中高度保守，分歧的衰老可能代表其他生物体细胞衰老的一般方案。
