The Natural Variation in Lifespans of Single Yeast Cells Is Related to Variation in Cell Size, Ribosomal Protein, and Division Time

Janssens, Georges E.; Veenhoff, Liesbeth M.

doi:10.1371/journal.pone.0167394

Cited by 56 publications

(79 citation statements)

References 46 publications

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“…For example, potential candidates include genes in other heterochromatic regions, such as subtelomeric genes that encode metabolic enzymes or have mitochondrial functions (33), or Sir2-repressed genes with prolongevity functions (34), or critical processes influenced by rDNA transcription, such as ribosomal biogenesis, a potential regulator of yeast aging (35,36). Interestingly, a recent study (37) demonstrated that aggregation of a cell-cycle regulator, but not the previously reported loss of silencing at HM loci (38), causes sterility in old yeast cells.…”

Section: Discussionmentioning

confidence: 99%

Multigenerational silencing dynamics control cell aging

Jin

O’Laughlin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Cellular aging plays an important role in many diseases, such as cancers, metabolic syndromes, and neurodegenerative disorders. There has been steady progress in identifying aging-related factors such as reactive oxygen species and genomic instability, yet an emerging challenge is to reconcile the contributions of these factors with the fact that genetically identical cells can age at significantly different rates. Such complexity requires single-cell analyses designed to unravel the interplay of aging dynamics and cell-to-cell variability. Here we use microfluidic technologies to track the replicative aging of single yeast cells and reveal that the temporal patterns of heterochromatin silencing loss regulate cellular life span. We found that cells show sporadic waves of silencing loss in the heterochromatic ribosomal DNA during the early phases of aging, followed by sustained loss of silencing preceding cell death. Isogenic cells have different lengths of the early intermittent silencing phase that largely determine their final life spans. Combining computational modeling and experimental approaches, we found that the intermittent silencing dynamics is important for longevity and is dependent on the conserved Sir2 deacetylase, whereas either sustained silencing or sustained loss of silencing shortens life span. These findings reveal that the temporal patterns of a key molecular process can directly influence cellular aging, and thus could provide guidance for the design of temporally controlled strategies to extend life span.replicative aging | single-cell analysis | microfluidics | chromatin silencing | computational modeling C ellular aging is generally driven by the accumulation of genetic and cellular damage (1, 2). Although much progress has been made in identifying molecular factors that influence life span, what remains sorely missing is an understanding of how these factors interact and change dynamically during the aging process. This is in part because aging is a complex process wherein isogenic cells have various intrinsic causes of aging and widely different rates of aging. As a result, static population-based approaches could be insufficient to fully reveal sophisticated dynamic changes during aging. Recent developments in single-cell analyses to unravel the interplay of cellular dynamics and variability hold the promise to answer that challenge (3-5). Here we chose the replicative aging of yeast S. cerevisiae as a model and exploited quantitative biology technologies to study the dynamics of molecular processes that control aging at the single-cell level.

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Section: Discussionmentioning

confidence: 99%

Multigenerational silencing dynamics control cell aging

Jin

O’Laughlin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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“…Furthermore, as metabolic allometry can explain complex biological phenomena, such as population density, lifespan and evolution rate, on an organismal level 25 [31,37], it seems reasonable to assume that cellular allometry may have profound, although unexplored, biological consequences. One such example is the cellular phenotype seen in aging cells, where mitochondrial activity is reduced [38,39] and cell size increased, at least in specific cell types [39,40]. The age-dependent decline in mitochondrial activity could, in theory, be partly due to the underlying cell size increase.…”

Section: Metabolic Allometry and Size Homeostasis In Dividing Cellsmentioning

confidence: 99%

Mitochondrial Function and Cell Size: An Allometric Relationship

Miettinen

Björklund

2017

Trends in Cell Biology

111

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Allometric scaling of metabolic rate results in lower total mitochondrial oxygen consumption with increasing organismal size. This is considered as a universal law in biology. Here, we discuss how allometric laws impose size dependent limits to mitochondrial activity at the cellular level. This cell size dependent mitochondrial metabolic activity results in nonlinear scaling of metabolism in proliferating cells, which can explain size homeostasis. The allometry in mitochondrial activity can be controlled through mitochondrial fusion and fission machinery, suggesting that mitochondrial connectivity can bypass transport limitations, the presumed biophysical basis for allometry. As physical size affects cellular functionality, cell size dependent metabolism becomes directly relevant for development, metabolic diseases and aging.

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“…Cell volume increases in aging and the increase per division is predictive for the lifespan of cells 37 . Because macromolecular crowding is directly linked to cell volume, we aimed to determine how the volume of the cytosol changes in aging and assessed aged cells on the ultrastructural level.…”

Section: Volume Distribution Of Cellular Compartments In Yeast Replicmentioning

confidence: 99%

“…For example, it was suggested that oversized yeast cells have reduced molecular density 35 . One of the most dramatic features of yeast is a marked increase in cell size [36][37][38] . Concomitantly, yeast organelles like vacuoles 39 , the nucleus (including nucleoli 40,41 ), and mitochondria 42 can exhibit changes in morphology.…”

Section: Introductionmentioning

confidence: 99%

A physicochemical roadmap of yeast replicative aging

Mouton

Thaller

Crane

et al. 2019

Preprint

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Author ContributionsConceptualization: S.N.M., A.J.B and L.M.V.; Investigation, Formal analysis: S.N.M. and D.J.T.; Methodology and Resources: M.M.C., I.L.R., and A.S.; Writing: S.N.M., A.J.B, and L.M.V.; Supervision: M.K., C.P.L., A.J.B, L.M.V. AbstractCellular aging is a multifactorial process that is characterized by a decline in homeostatic capacity, best described at the molecular level. Physicochemical properties such as pH and macromolecular crowding, are essential to all molecular processes in cells and require maintenance. Whether a drift in physicochemical properties contributes to the overall decline of homeostasis in aging is not known. Here we show that the cytosol of yeast cells acidifies modestly in early aging and sharply after senescence. Using a macromolecular crowding sensor optimized for long-term FRET measurements, we show the macromolecular crowding changes less in longer-lived cells in contrast to shorter-lived cells. While the average pH and crowding levels change only modestly with aging, we observe drastic changes in organellar volume, leading to crowding on the µm scale, which we term organellar crowding. Our measurements provide an initial framework of physicochemical parameters of replicatively-aged yeast cells.

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The Natural Variation in Lifespans of Single Yeast Cells Is Related to Variation in Cell Size, Ribosomal Protein, and Division Time

Cited by 56 publications

References 46 publications

Multigenerational silencing dynamics control cell aging

Multigenerational silencing dynamics control cell aging

Mitochondrial Function and Cell Size: An Allometric Relationship

A physicochemical roadmap of yeast replicative aging

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