Cell aging preserves cellular immortality in the presence of lethal levels of damage

Abstract

Cellular aging, a progressive functional decline driven by damage accumulation, often culminates in the mortality of a cell lineage. Certain lineages, however, are able to sustain longlasting immortality, as prominently exemplified by stem cells. Here, we show that Escherichia coli cell lineages exhibit comparable patterns of mortality and immortality. Through single-cell microscopy and microfluidic techniques, we find that these patterns are explained by the dynamics of damage accumulation and asymmetric partitioning between daughter cells. At low damage accumulation rates, both aging and rejuvenating lineages retain immortality by reaching their respective states of physiological equilibrium. We show that both asymmetry and equilibrium are present in repair mutants lacking certain repair chaperones, suggesting that intact repair capacity is not essential for immortal proliferation. We show that this growth equilibrium, however, is displaced by extrinsic damage in a dosagedependent response. Moreover, we demonstrate that aging lineages become mortal when damage accumulation rates surpass a threshold, whereas rejuvenating lineages within the same population remain immortal. Thus, the processes of damage accumulation and partitioning through asymmetric cell division are essential in the determination of proliferative mortality and immortality in bacterial populations. This study provides further evidence for the characterization of cellular aging as a general process, affecting prokaryotes and eukaryotes alike and according to similar evolutionary constraints.

Allocation of gene products to daughter cells is determined by the age of the mother in single Escherichia coli cells

“…The correlation between elongation rate and fluorescence is consistent with early reports that show positive correlations between ribosome levels, which produce proteins, and growth rate [29,34]. It is also consistent with figures 4 and 5 that show that asymmetry between daughter cells is always higher when originating from old mothers, which allocate more of the damaged proteins to her old daughter [18] and more newly synthesized proteins to her new daughter.…”

“…In other words--the more different the poles, the more different the daughters. Thus, a substantial proportion of the variation of expressed gene products previously attributed to stochasticity in single E. coli cells results from the deterministic Because elongation rates in E. coli have a deterministic asymmetric component of variance [17,18], the cells quantified for fluorescence in figure 4 were further examined to determine whether they manifested a similar asymmetry and variance pattern for elongation rates and whether GFP and elongation rates were correlated. Elongation rates were measured (see Material and Methods) for all daughters and grouped by old and new mothers.…”

“…Recent results have shown that the growth rate of single and clonal bacterial cells is also highly stochastic [17][18][19]. However, the growth rates were found to have a significant deterministic component that is controlled by the asymmetrical partitioning of non-genetic damage, such as oxidized or mistranslated proteins, by a mother bacterium to its two daughters.…”

“…The old pole and old daughters are more likely to harbour aggregates of damaged and synthetically misfolded proteins, and aggregate size is negatively correlated with cell growth rate [25,27]. If dnaK, the gene responsible to dismantling aggregates for repair, is knocked out in E. coli lineages of new daughters survive while lineages of old daughters perish [18]. Although early investigations reported that damage rates in standard laboratory culture were too low to generate an asymmetry between old and new daughters [23,28], follow-up studies have shown that a difference is detectable with improved microscopy and larger sample sizes [17,18,26].…”

Damage Repair versus Aging in an Individual-Based Model of Biofilms

“…Second, we neglect damage that had not been repaired before segregation or that would be prohibitively expensive to repair, since the work of Lin Chao’s group has covered this well. They have shown that damage segregation under constant environmental conditions leads to separate steady-state levels of damage in cells of both old and young lineages, meaning that growth rate and mortality of cells do not change over divisions ( 42 , 43 , 94 – 97 ). (Since there is no trend of deterioration and the replication of young and old lineages does not fit a germline-soma distinction, it is probably better to refer to this as damage homeostasis rather than senescence.)…”