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When cells grow older

The mother cell (green) is locked in a micro-cavity and unidirectional budding enable to follow the fate of its daughter cells.

Aging yeast cells undergo a sharp entry into senescence unrelated to the loss of mitochondrial membrane potential.

Fehrmann S(1), Paoletti C(1), Goulev Y(1), Ungureanu A(2), Aguilaniu H(3), Charvin G(4).

Cell Rep Dec. 26, 2013

Dec. 12, 2013

Fundamental mechanisms of cellular aging are poorly understood so far, notably because of the difficulty to track the fate of single cells over time. Gilles Charvin’s team has developed a new technique to overcome this problem. This innovative method has enabled to test and challenge a widely accepted model on the phenomenon of replicative aging, i.e. linked to successive cell divisions. These results are published on December 12th in Cell Reports.


Permanently within living beings, cells divide, others die. To study this phenomenon of aging (also called senescence), yeast is a prominent model organism. Unicellular, its asymmetric budding facilitates the tracking of mother cells (which give birth to daughter cells) during their successive divisions until their death that occurs after around 25 divisions. For twenty years, researchers have tried through this model to understand the mechanisms of aging at the cellular level. The technique traditionally used was based on a microdissection experiment which is particularly long and tedious and which only allows to determine the age of cell death.


Locked in a microcavity
Gilles Charvin’s team has developed an innovative method that aims to track in real time the fate of a single yeast cell from birth to death under the microscope. For this purpose, they set up a microstructured environment with tiny cavities having a width of 6 microns, thus allowing the passage of only one cell. Based on the known property of yeast that the budding of the mother cell is always in the same direction, the researchers have managed to block a mother cell at the end of the cavity and observe its fate during successive divisions. This technique, coupled with and automatized image processing, has allowed Gilles Charvin’s team to monitor the dynamics of entry into replicative senescence.


Dynamics of cellular aging
Until now, researchers thought that the decline of a cell until its death was progressive. Now researchers have shown that in reality, cells goes suddenly from a "healthy" condition with regular cycles every 1h30, to a senescent state with very variable cycles between 4 and 10 hours. The moment when the cell begins to enter into long cycles and that marks the beginning of senescence has been named "Senescence entry point".


A classic model challenged
Thanks to this new technique, the researchers were able to test some hypothesis previously put forward to explain the entry into senescence. In particular, they showed that the commonly accepted model of Dan Gottschling (Fred Hutchinson Cancer Research Center, USA), according to which a loss of membrane potential in the mitochondria is the cause of cell senescence, was wrong. However, researchers have actually demonstrated significant changes at the mitochondrial level, leading to clustering of mitochondria during cell budding, and then their decompaction/segregation at the time of division.


Gilles Charvin explains that "our predecessors have been misled by the heterogeneity of cells. Indeed, while the average life duration of cells is 20-25 generations, this number actually oscillates between 10 and 40, which makes the concept of "young" or "old" cell more complicated... Only a quantitative approach based on the analysis of the fate of single cells can reveal the abrupt nature of the entry into senescence. Concerning the results of Dan Gottschling, their main potential artefact of their methodology was to use a yeast strain with a high propensity to lose its membrane potential, which is not at all the case for the vast majority of wild strains and the one that we use in our study". These results are very interesting in several aspects. They first provide a very powerful methodology to easily study the replicative aging of cells and provide an essential insight to better understand the future functional studies.

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