Cellular aging is a complex biological process, in which genetically identical cells show heterogeneous aging behavior. While it is generally believed that aging is driven by accumulation of genetic and cellular damage, molecular regulation of the aging process remains largely unclear. As aging studies in mammals are prohibitively long and resource-intensive, much of the progress in understanding human aging comes from studies in model organisms, such as the budding yeast. The proposed project will develop novel technologies to enable visualization of the aging process in a large number of single living cells in a dynamically controlled environment. These new technologies will be combined with computational modeling and synthetic biology approaches to advance the fundamental scientific understanding of the aging process in living organisms. The broader impact goal of this project is to foster the growth of the emerging field of quantitative biology and to train the new generation of scientists capable of integrating experiments with quantitative analysis. In particular, a new summer experimental program focusing on hands-on training in quantitative analysis of aging is designed to expose undergraduate students to cutting-edge quantitative biology technologies at very early-stages of their scientific training.
Yeast replicative aging has been intensively studied for a half century and serves as a uniquely tractable model for the aging of many mitotically active cell types in mammals. However, a mechanistic understanding about the regulation of yeast aging remains limited. This is in part due to the lack of technologies to directly monitor molecular processes in living cells during aging. The investigator's research group has developed novel microfluidics and single-cell imaging technologies that enable visualization of the aging process in single yeast cells in a fully automated fashion. The objective is to combine these transformative methodologies with synthetic biology to engineer the aging process in single cells. The project will focus on engineering the regulation of chromatin silencing, which protects cells from genomic instability, a major causal factor of cellular aging. The dynamics of chromatin silencing in single cells will be measured using novel fluorescent reporters to quantitatively correlate these parameters with the aging process. The expectation is that this approach will allow the prediction of the aging stage and remaining lifespan of a living cell. Quantitative experiments will be integrated with modeling and synthetic biology to further investigate the dynamic regulation of cellular aging by chromatin silencing. This work will for the first time reveal the dynamic regulation of chromatin stability during aging at the single-cell level and will provide new mechanistic insights into the cause of cellular aging and the source of cell-cell variability in lifespans. The combined approaches could potentially lead to the creation of synthetic yeast cells with much extended longevities.
