Tsai Kevin, Zhou Zhen, Yang Jiadong, Xu Zhiliang, Xu Shixin, Zandi Roya, Hao Nan, Chen Weitao, Alber Mark
Department of Mathematics, University of California, Riverside, CA, United States of America.
Interdisciplinary Center for Quantitative Modeling in Biology, University of California, Riverside, CA, United States of America.
bioRxiv. 2024 Feb 29:2024.02.29.582376. doi: 10.1101/2024.02.29.582376.
Understanding the mechanisms of cellular aging processes is crucial for attempting to extend organismal lifespan and for studying age-related degenerative diseases. Yeast cells divide through budding, providing a classical biological model for studying cellular aging. With their powerful genetics, relatively short lifespan and well-established signaling pathways also found in animals, yeast cells offer valuable insights into the aging process. Recent experiments suggested the existence of two aging modes in yeast characterized by nucleolar and mitochondrial declines, respectively. In this study, by analyzing experimental data it was shown that cells evolving into those two aging modes behave differently when they are young. While buds grow linearly in both modes, cells that consistently generate spherical buds throughout their lifespan demonstrate greater efficacy in controlling bud size and growth rate at young ages. A three-dimensional chemical-mechanical model was developed and used to suggest and test hypothesized mechanisms of bud morphogenesis during aging. Experimentally calibrated simulations showed that tubular bud shape in one aging mode could be generated by locally inserting new materials at the bud tip guided by the polarized Cdc42 signal during the early stage of budding. Furthermore, the aspect ratio of the tubular bud could be stabilized during the late stage, as observed in experiments, through a reduction on the new cell surface material insertion or an expansion of the polarization site. Thus model simulations suggest the maintenance of new cell surface material insertion or chemical signal polarization could be weakened due to cellular aging in yeast and other cell types.
了解细胞衰老过程的机制对于延长生物体寿命以及研究与年龄相关的退行性疾病至关重要。酵母细胞通过出芽进行分裂，为研究细胞衰老提供了一个经典的生物学模型。酵母细胞具有强大的遗传学特性、相对较短的寿命以及在动物中也存在的成熟信号通路，为衰老过程提供了有价值的见解。最近的实验表明，酵母中存在两种衰老模式，分别以核仁衰退和线粒体衰退为特征。在本研究中，通过分析实验数据表明，演变成这两种衰老模式的细胞在年轻时表现不同。虽然在两种模式中芽都呈线性生长，但在整个生命周期中持续产生球形芽的细胞在年轻时控制芽大小和生长速率方面表现出更高的效率。开发了一个三维化学 - 力学模型，并用于提出和测试衰老过程中芽形态发生的假设机制。经实验校准的模拟表明，在出芽早期，一种衰老模式中的管状芽形状可以由极化的Cdc42信号引导在芽尖局部插入新材料而产生。此外，如实验观察到的，在后期管状芽的纵横比可以通过减少新细胞表面材料的插入或扩大极化位点来稳定。因此，模型模拟表明，由于酵母和其他细胞类型中的细胞衰老，新细胞表面材料插入或化学信号极化的维持可能会减弱。
