US researchers studying yeast cells found that ageing cells able to retain a group of proteins that ferry compounds across cellular membranes and get rid of toxic waste have a longer lifespan in that they can produce more copies of themselves compared with cells that lose their waste disposal proteins; they also hope their finding may help us better understand stem cells and cancer cells.
You can read how Dr Rong Li and colleagues at the Stowers Institute for Medical Research in Kansas City, Missouri, investigated the role of multidrug resistance (MDR) protein families in cell ageing in a study published online on 25 July in the journal Nature Cell Biology.
Studies have shown time and again that cellular ageing is linked to the accumulation of harmful agents, wrote the researchers in their background information, but what is unclear is the extent to which decline in beneficial agents that do not readily replenish themselves also contributes to ageing.
Multidrug resistance (MDR) proteins are so-named because researchers discovered they get rid of anticancer drugs in cancer cells; it wasn’t till later that further research revealed this was just part of their overall role of ferrying compounds in and out of cells, including disposal of waste and toxins.
In this study, Li and colleagues found that yeast cells that did not have their full complement of MDR proteins had a shorter replicative lifespan: they could not produce as many daughter cells, but when they inserted genes to give them back their full complement of MDR proteins they regained their ability to produce more daughter cells, in effect extending their lifespan.
So how does the ageing yeast cell lose its MDR proteins?
Yeast cells don’t divide evenly in the same way as for example gut or skin cells, their replication is “asymmetric”: a mother cell gives rise to new “bud” or “daughter” that is different in several ways.
Others studies have already shown that when yeast cells divide and make new daughter cells, the mother cells keep the old MDR proteins (including any damaged ones), and give the daughter cells newly synthesized ones. Some have gone as far as to suggest that the mother cells’ lifespan is linked to the accumulation of damaged MDR proteins.
As Li explained to Nature News:
“The mother is very altruistic and keeps all this bad stuff to herself.”
To better understand what was happening to the MDR proteins inside the mother cells, Li and colleagues measured the rate of loss of MDR protein function and then produced a model of their dynamics. The model predicted that the MDR proteins lose nearly all their function as the mother cells get to the end of their reproductive livespan.
So to test the idea that perhaps the presence of fully functioning MDR proteins is what extends cell lifespan, they started to switch genes on and off.
First they made three mutant strains of yeast cells, each lacking an MDR protein gene and showed that depending on which gene was switched off, the ability of the defective mother cell to produce daughters varied between 1 and 66 per cent.
Then, when they added back the MDR protein genes one at a time, depending on which gene they added, the mother cell lifespan went up between 10 and 20 per cent.
The researchers stressed that their finding does not rule out other ways that might contribute to cell ageing, such as build up of toxins.
MDR proteins get rid of toxic waste in cells, so if they deteriorate, toxins build up.
“It’s two sides of the same coin,” Li told Nature News.
Another way of slowing down cell ageing could be to slow down the build up of toxins, for instance by calorie restriction. This would put less stress on the MDR proteins, raising the odds that they deteriorate less rapidly.
“Ageing is not just a single thing. It’s a combination of processes that affect each other,” said Li.
Li said their findings may also help us better understand stem cells and why cancer cells seem immortal. Stem cells divide asymmetrically like yeast cells, so perhaps they also give their youthful offspring newly synthesized MDR proteins, and cancer cells have an abundance of MDR proteins.
“Asymmetrically inherited multidrug resistance transporters are recessive determinants in cellular replicative ageing.”
Amr Eldakak, Giulia Rancati, Boris Rubinstein, Parama Paul, Veronica Conaway & Rong Li.
doi:10.1038/ncb2085
Additional source: NatureNews.
Written by: Catharine Paddock, PhD