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Cell Syst. 2019 Mar 27;8(3):242-253.e3. doi: 10.1016/j.cels.2019.02.002. Epub 2019 Mar 6.

Divergent Aging of Isogenic Yeast Cells Revealed through Single-Cell Phenotypic Dynamics.

Author information

1
BioCircuits Institute, University of California, San Diego, La Jolla, San Diego, CA 92093, USA.
2
Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, San Diego, CA 92093, USA.
3
Department of Bioengineering, University of California, San Diego, La Jolla, San Diego, CA 92093, USA.
4
Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, San Diego, CA 92093, USA; UCSD Moores Cancer Center, University of California, San Diego, La Jolla, San Diego, CA 92093, USA.
5
BioCircuits Institute, University of California, San Diego, La Jolla, San Diego, CA 92093, USA. Electronic address: ltsimring@ucsd.edu.
6
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; Department of Bioengineering, University of California, San Diego, La Jolla, San Diego, CA 92093, USA. Electronic address: jhasty@eng.ucsd.edu.
7
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. Electronic address: nhao@ucsd.edu.

Abstract

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.

KEYWORDS:

caloric restriction; cell fate decision; cellular aging; computational modeling; dynamics; microfluidics; single-cell analysis; sirtuins; stochastic simulations; time-lapse microscopy

PMID:
30852250
PMCID:
PMC6514117
[Available on 2020-03-27]
DOI:
10.1016/j.cels.2019.02.002

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