Aging, mortality, and the fast growth trade-off of Schizosaccharomyces pombe

Abstract

Replicative aging has been demonstrated in asymmetrically dividing unicellular organisms, seemingly caused by unequal damage partitioning. Although asymmetric segregation and inheritance of potential aging factors also occur in symmetrically dividing species, it nevertheless remains controversial whether this results in aging. Based on large-scale single-cell lineage data obtained by time-lapse microscopy with a microfluidic device, in this report, we demonstrate the absence of replicative aging in old-pole cell lineages of Schizosaccharomyces pombe cultured under constant favorable conditions. By monitoring more than 1,500 cell lineages in 7 different culture conditions, we showed that both cell division and death rates are remarkably constant for at least 50–80 generations. Our measurements revealed that the death rate per cellular generation increases with the division rate, pointing to a physiological trade-off with fast growth under balanced growth conditions. We also observed the formation and inheritance of Hsp104-associated protein aggregates, which are a potential aging factor in old-pole cell lineages, and found that these aggregates exhibited a tendency to preferentially remain at the old poles for several generations. However, the aggregates were eventually segregated from old-pole cells upon cell division and probabilistically allocated to new-pole cells. We found that cell deaths were typically preceded by sudden acceleration of protein aggregation; thus, a relatively large amount of protein aggregates existed at the very ends of the dead cell lineages. Our lineage tracking analyses, however, revealed that the quantity and inheritance of protein aggregates increased neither cellular generation time nor cell death initiation rates. Furthermore, our results demonstrated that unusually large amounts of protein aggregates induced by oxidative stress exposure did not result in aging; old-pole cells resumed normal growth upon stress removal, despite the fact that most of them inherited significant quantities of aggregates. These results collectively indicate that protein aggregates are not a major determinant of triggering cell death in S. pombe and thus cannot be an appropriate molecular marker or index for replicative aging under both favorable and stressful environmental conditions.

Guidelines and recommendations on yeast cell death nomenclature

“…In any case, we suggest determining the kinetics of the cell death process (see above) to accurately resolve the appearance of these subpopulations. In general, any approaches that facilitate monitoring death scenarios time-dependently represent a helpful improvement, for instance replicative age-associated changes using microfluidic platforms 189 190 191 192 193 .…”

Age structure landscapes emerge from the equilibrium between aging and rejuvenation in bacterial populations

“…Nonetheless, despite a succession of reports on bacterial aging 3 – 6 , 8 – 11 and the identification of similar asymmetry in other systems 12 – 15 , the validity and significance of the phenomenon remains controversial. Although protein aggregates are strongly biased toward old poles in E. coli and reportedly correlate with functional decline 6 , 8 , 9 , 16 , this association was often found to be equivocal in similar systems, such as fission yeast 13 , 17 . Studies in both E. coli and fission yeast suggested that aging is a consequence of extrinsic damage 11 , 13 , configuring their divisional asymmetry as a conditional strategy 18 as opposed to a deterministic process.…”

Intrinsic growth heterogeneity of mouse leukemia cells underlies differential susceptibility to a growth-inhibiting anticancer drug

“…Indeed, occasional cell deaths were observed (S1 Video), and the death rate was found to be constant (2.2 ⇥ 10 3 h 1 , corresponding to roughly 2% chance of death per generation) ( Fig 1F). Cell death under favorable growth conditions with low frequency has also been reported in bacteria and fission yeast [21][22][23], which presumably reflects an accidental loss of cellular homeostasis or stochastic triggering of signal transduction pathways leading to cell death. The constant division and death rates confirmed that the cells experienced conditions of balanced growth in the microfluidic device.…”

“…To monitor single L1210 cells for multiple generations, we fabricated a mammalian-optimized version of mother machine microfluidic device [8,[21][22][23] (Fig 1A-C). The mother machine was originally developed to analyze single bacterial cells [21] and then adapted for studying eukaryotic cells [8,22,23]. In these devices, individual cells are placed at the closed end of the growth channels.…”