Published online 25 July 2010 | Nature | doi:10.1038/news.2010.373

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Longevity of cells could be linked to levels of cellular pumps that get rid of toxic cell products.

Yeast cells that lack multidrug resistance proteins produce fewer daughters. Carolyn Larabell, University of California, San Francisco, and the Lawrence Berkeley National Laboratory

A family of proteins that pump molecules across the cell membrane may help to explain why yeast cells, and perhaps the cells of other organisms, are not able to go on producing copies of themselves forever. The same proteins may also partly explain how stem and cancer cells keep dividing.

Yeast cells, much like our own cells, have a finite ability to reproduce themselves. A 'mother' cell can only produce 20-30 'daughters' before it loses the ability to replicate and dies. Scientists have proposed a number of explanations for why this might be, but they have yet to pin down the exact mechanism. The latest study, published today in Nature Cell Biology, implicates a family of proteins called multidrug resistance proteins1. The authors say the finding may also help to explain stem cells' ability to keep replicating.

Multidrug resistance (MDR) proteins are best known for helping cancer cells expel anticancer drugs — hence their name — but they also ferry compounds in and out of normal cells. Rong Li and colleagues at the Stowers Institute for Medical Research in Kansas City, Missouri, found that yeast lacking certain MDR proteins have a shorter reproductive lifespan; they produce fewer daughter cells. Yeast engineered to contain more of these pumps, however, can produce more daughters.

Scientists have long used the single-celled baker's yeast (Saccharomyces cerevisiae) as a model for studying ageing. Its cells don't divide like skin cells or gut cells, however. Division is asymmetric and small new cells 'bud' off the mother cell, giving rise to a 'mother' and a 'daughter' that aren't identical. Previous studies have shown that, during division, the mother conserves damaged proteins and other cellular components that could prove harmful to the bud. "The mother is very altruistic and keeps all this bad stuff to herself," Li says. Indeed, some research groups have posited that the mother's finite reproductive capability is the result of accumulating these damaged and toxic compounds.

Pump action

Li and her colleagues, however, had another hypothesis. They found that yeast division also results in an unequal distribution of MDR proteins. The mother cell retains the original MDR proteins while the bud gets young, newly formed MDR proteins. Because the mother's supply is never replenished, she has to rely on the pool of MDR proteins that she's born with, Li says.

“The mother is very altruistic and keeps all this bad stuff to herself.”



Over time these proteins decay. Some lose only part of their function; others may stop working altogether. Li and her colleagues measured the decay rate and developed a model to better understand the dynamics of MDR proteins during a cell's life. The model suggested that these proteins lose most of their function just as the cell is coming to the end of its reproductive life. We started to get the idea that "maybe these proteins are what's limiting the lifespan of these cells," Li says.

If the loss of MDR proteins does contribute to ageing, then cells that can't make these proteins should have shorter lifespans. To test this idea, the researchers created three mutant strains of yeast. Each one lacked a gene coding for a particular MDR protein. Losing one MDR gene reduced the number of daughters a cell could produce by between 11 and 66%, depending on which gene the researchers turned off.

Next the researchers added an extra copy of each gene. "This is really a very small variation in expression level," Li says. Still it had an effect. The researchers saw a 10-20% increase in lifespan.

Stem-cell link

The new mechanism doesn't necessarily preclude other pathways that have been linked to ageing, such as the build-up of toxins. MDR proteins help rid cells of toxins, so as they begin to fail, toxins could accumulate even faster. "It's really two sides of the same coin," Li says.

The MDR pathway might also be tied to the effects of calorie restriction. Restricting dietary calorie intake seems to be a sure-fire way of increasing longevity in many organisms. If you limit metabolism, that could reduce "the generation of a lot of the toxic compounds," Li says. "Ageing is not just a single thing. It's a combination of processes that affect each other," she adds.

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Brian Kennedy, chief executive of the Buck Institute for Age Research in Novato, California, says the study "raises a new and compelling hypothesis for what's causing ageing in yeast". What's more, he adds, this family of proteins is conserved in other organisms so may be involved in the ageing process more generally. "There's a lot of compelling data to support the model," he says.

Just how this finding might translate to humans, however, is not yet clear. Stem cells also undergo asymmetric division. The study "raises the intriguing possibility that a similar mode of regulation could influence stem-cell senescence during human ageing," says Matt Kaeberlein, at the University of Washington Medical School in Seattle, who investigates longevity in yeast, worms and mice.

Li says the MDR mechanism might also help explain why cancer cells, many of which are stuffed with MDRs, are seemingly immortal.