End-of-life cell cycle arrest contributes to stochasticity of yeast replicative aging

Abstract

There is growing evidence that stochastic events play an important role in determining individual longevity. Studies in model organisms have demonstrated that genetically identical populations maintained under apparently equivalent environmental conditions display individual variation in lifespan that can be modeled by the Gompertz-Makeham law of mortality. Here we report that within genetically identical haploid and diploid wild type populations, shorter-lived cells tend to arrest in a budded state, while cells that arrest in an unbudded state are significantly longer-lived. This relationship is particularly notable in diploid BY4743 cells, where mother cells that arrest in a budded state have a shorter mean lifespan (25.6 vs. 35.6) and larger coefficient of variance with respect to individual lifespan (0.42 vs. 0.32) than cells that arrest in an unbudded state. Mutations that cause genomic instability tend to shorten lifespan and increase the proportion of the population that arrest in a budded state. These observations suggest that randomly occurring damage may contribute to stochasticity during replicative aging by causing a subset of the population to terminally arrest prematurely in the S or G2 phase of the cell cycle.

Microfluidic technologies for yeast replicative lifespan studies

“…For example, researchers found that delays in nuclear segregation during cytokinesis occur rarely during a cell’s lifetime but increase dramatically in frequency after division speeds slow with age 32 . Researchers also correlated heterogeneity in end-state cell morphology, which had been previously reported by microdissection studies 38,39 , with molecular properties of those cells. Cells trapped under a PDMS column that die in a round (as opposed to elongated) morphology are shorter-lived, display more pronounced measures of mitochondrial dysfunction, and have higher Hsp104 promoter activity at death 9,10 .…”

Inactivation of Yeast Isw2 Chromatin Remodeling Enzyme Mimics Longevity Effect of Calorie Restriction via Induction of Genotoxic Stress Response

“…Given our recent findings of a correlation between short lifespan and S phase arrest in yeast terminal state (Delaney et al, 2013), it seems highly unlikely that a defect in DNA replication via reduced Isw2 would promote longevity.…”

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging

“…Rad53 has been previously implicated in aging (Delaney et al, 2013; Schroeder et al, 2013; Weinberger et al, 2010) but not linked to the response to DR. Redistribution of Los1 to the cytoplasm in response to DR was prevented in cells lacking RAD53 (p=0.1, Figure 4A, Supplemental Table S5, related to Figure 4).…”