More Insight into the Relationship Between Cell Size and Cell Senescence

barbara

Pioneer Founding member
FightAging! 12-29-19

https://www.fightaging.org/archives/2019/12/more-insight-into-the-relationship-between-cell-size-and-cell-senescence/

Senescent cells accumulate with age and cause considerable disruption of metabolism and tissue function. This is an important contribution to aging, and there is thus funding and interest for continued research into senescent cell biochemistry. Senescent cells are very different from normal cells in many respects, but one of the more striking is that they are much larger. One group has used this to build a microfluidics platform capable of counting and sorting senescent cells, but we may well ask why exactly it is that senescent cells become large in comparison to normal cells. A hypothesis is offered in this popular science article.

Biologists have known since 1961 that normal human cells will only divide 40 to 60 times before ceasing to replicate - a constraint known as the Hayflick limit. Recent research shows that this limit may be defined by a cell's physical size. When Leonard Hayflick first described this senescence phenomenon, he pointed out that these senescent cells were actually huge. Researchers have shown that when cells below the Hayflick limit are induced to grow larger than they should be, they have all the characteristics of senescent cells.
But why do cells get so large, and why should that increased size cause a cell to senesce and ultimately stop dividing? The explanation is suggested to lie in how cells repair damage to the DNA coiled in their chromosomes. Natural DNA damage occurs constantly, and cells must periodically pause the cell cycle to fix it. However, other processes inside the cell - such as building proteins and other biomolecules - don't pause during DNA repair. As a result, every time the cell cycle stops, the cell gets a little larger. If a cell becomes too large, its own genes can't direct the production of enough protein to sustain the cell's function. Cellular functions decline and the cell becomes senescent.
One clue supporting this connection between size and senescence is that doubling the number of genes inside the cell - which doubles the amount of proteins it builds to sustain itself - reverses the senescence process. Furthermore, when using rapamycin to inhibit cells' ability to manufacture proteins (and thus get larger) while paused to repair DNA damage, the cells stay small and avoid senescence - they don't lose their replicative potential. "We've known for a very long time that DNA damage causes senescence, but nobody could explain it. I think we've come up with a proposal for why this is happening - cells get larger during the time they arrest in the cell cycle to repair the damage, and when they are large they lose their functionality. This appears to be universally true from yeast to humans."
 
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