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

cellular aging damage accumulation asymmetric partitioning

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#1 Engadin

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Posted 04 June 2019 - 02:21 PM


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 long-lasting 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 dosage-dependent 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.

 

 

Introduction

 

Aging, or the progressive loss of function at the macromolecule, tissue, organ, or individual level, is largely driven by the deterioration of intracellular processes. Accordingly, the hallmarks of the aging phenotype—such as telomeric attrition, mitochondrial dysfunction, loss of proteostasis, and genomic instability—which have been well characterized by previous studies [1], reveal conserved genetic and biochemical pathways at the cellular level. Considering cellular aging as a baseline for the study of aging as a general process, we can summarize its mechanisms as the gradual intracellular accumulation of damage from various sources, along with a decreasing repair capacity. Furthermore, excessive damage accumulation within a cell lineage may lead to cellular senescence, in which individual cells cease replicating, and the lineage transitions to a mortal state [24].

 

The cellular aging process encompasses both multi- and unicellular organisms, such as yeast, diatoms, and even bacteria [58]. Due to the traditional view of unicellular prokaryotes as being functionally immortal, these organisms are often overlooked in the discussion of cellular aging. However, research in bacterial aging stands out for offering quantitative approaches to data collection and analysis, coupled with technical improvements on single-cell microscopy, which have detailed the aging phenotype and its progression. Although bacteria do not possess some of the eukaryotic aging targets, like telomeres and mitochondria, they are sensitive to stresses that induce nongenetic damage accumulation, such as oxidation and disruptions in protein folding [9,10]. Stressed bacteria accumulate misfolded proteins in the form of polar-localized aggregates [1114], thus displaying loss of proteostasis. Repair occurs in a slow and energy-consuming fashion, in which chaperone proteins such as DnaK and ClpB mediate the disaggregation and unfolding of damaged proteins [10,12]. Additionally, the potential prokaryotic origin of mitochondria raises the possibility of regarding bacterial aging as a model for mitochondrial dysfunction, a noted hallmark of aging [1].

 

Besides aggregating and repairing damaged components, bacterial populations have developed another remarkable strategy to handle nongenetic damage. Experimental data from long-term microscopy of bacterial lineages revealed that, in the presence of intracellular damage, each cellular division produces 2 physiologically asymmetric daughters [8,11,1517]. This asymmetry is generated because the damage harbored by the mother is biased toward the old cell pole [11,12], causing the daughter that inherits this pole—termed the old daughter—to age. Its sibling, on the other hand, rejuvenates through the inheritance of a lower damage load, being called the new daughter. Therefore, by partitioning damage with asymmetry, bacterial populations engage in a trade-off in which the fast growth of new daughters is sustained at the expense of the declining cellular function of old daughters. Mathematical models and computational simulations were developed to estimate the advantage of asymmetry, in contrast with a symmetric control population—a hypothetical scenario in which both daughters display equal physiology [18]. The models have shown that asymmetry is evolutionarily advantageous because it increases the variance of elongation rates, which in turn increases the efficiency of natural selection and the mean fitness of the lineage. Diverse studies are beginning to show that asymmetric partitioning is not unique to bacteria but an advantageous mechanism for the progression of cell lineages. In fact, this process was recently observed in neural, embryonic, and germline stem cells [1921], in which damage allocation plays a central role in self-renewal capacity, fate determination, and somatic sequestration of damage.

 

A better understanding of how the key features of aging are interconnected requires the eventual development of conceptual and mathematical models that can integrate with experimental studies the growth and aging of individual organisms or cells. Unicellular systems, such as bacteria, satisfy all these requirements. Here, we show that the maintenance of proliferative immortality in Ecoli lineages depends on the physiological equilibrium produced by contrasting damage accumulation and asymmetric partitioning. We demonstrate that unstressed lineages accumulate damage produced by standard respiration levels, subsequently partitioning this load with a level of asymmetry that allows for the dilution of damage within both new and old daughters. We show that Ecoli mutants with decreased repair capacity also exhibit asymmetric new and old daughters, reaching distinct states of growth equilibrium. Furthermore, bacterial aging responds with a positive dosage relationship to an external damaging agent, which progressively disrupts proteostasis by increasing damage accumulation rates and disrupting asymmetry. With a sufficiently elevated stress level, the damage accumulation within old lineages surpasses their immortality threshold, leading these lineages to arrest division and become mortal. However, due to asymmetric partitioning, new lineages within the same population retain proliferative immortality. Our results show that the appropriate model and system can contribute to identifying the dynamics of mortality and immortality in the context of cellular aging.

 

 

S O U R C E :   PLOS Biology


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