One s risk for cancer increases greatly as a person ages. One reason why suggests that aging might increase chromosome instability a hallmark feature of tumor cells. Maternal yeast cells of a certain age enter a state in which they produce daughter cells that are far more prone to mutation.

A paper in the current issue of Science, dated Sept. 26, 2003, is titled An age-induced switch to a hyper-recombinational state. Its co-authors are Michael McMurray and Daniel Gottschling, molecular and cell biologists at the University of Washington in Seattle.

Age may be the greatest carcinogen, the Science paper leads off. Cancer incidence increases exponentially near the end of human life. Chromosomal abnormalities are a hallmark of most tumors, it continues, and there is widely held opinion that genomic instability is a prerequisite for tumorigenesis. In older individuals, there is evidence for increased genomic instability, even in noncancerous cells.

To develop a mechanistic understanding, the Science paper noted, we asked whether such a phenomenon occurs in a model biological system the budding yeast Saccharomyces cerevisiae.

An accompanying editorial is briefly headed, An age of instability. It is written by molecular geneticist David Sinclair at Harvard Medical School in Boston. He makes the opening point that if there s one thing we ve learned from the last 50 years of research on baker s yeast, it is not to underestimate how much this tiny fungus can tell us. We now know that yeast provide key insights into such complex human disorders as variant Creutzfeld-Jacob disease [mad-cow disease], Parkinson s disease and cancer.

Among Scientists, Less Skepticism Called For

In a 1959 issue of Nature, the authors tried to convince a skeptical scientific community that this modest unicellular microorganism might be useful for understanding human aging. Less skepticism, Sinclair said, should greet the report by McMurray and Gottschling. These investigators show that yeast-cell aging is accompanied by increased genetic instability a hallmark of cancer. This finding might help researchers to understand the link between cancer and old age in humans.

In the final decades of life, Sinclair pointed out, one s chance of developing cancer rises exponentially. In fact, at age 70 that risk is more than 10 times the risk three decades earlier. It is tempting to think, Sinclair continued, that cancer occurs later in life because of a steady accumulation of mutations. Certainly, cells isolated from the elderly have more chromosomal abnormalities than cells from the young.

But the story is not so simple, Sinclair went on, because rates of spontaneous mutation are too low to account for the extensive genome rearrangement found in tumors. Experiments in mice, he notes, have confirmed the suspicion that mutation rates increase with age. He also noted that the difficulty of studying aging in mammals makes the new work in yeast appealing.

Does Yeast Mimic Aging Mice In Mutation Rate?

The Seattle team set out to determine whether yeast cells, like mammalian ones, also experience an age-dependent increase in mutation rate. They engineered yeast mother cells so that the colonies produced by their daughters served as miniature colored pie charts that displayed the genetic history of the colony s founders.

One advantage of yeast, Sinclair observed, is their short life span. The life span of budding yeast is typically defined as the number of daughter cells an individual mother cell produces before dying. A yeast cell divides about 20 times, approximately once every two hours. A major disadvantage is that determining the life span of microscopic cells is no easy task. A researcher must spend many days sampling cells with a fiberoptic needle connected to a microdissection apparatus. In the new work, the time of birth for each daughter cell also was recorded.

Some long-lived cells produced more than 60 offspring requiring the investigators to pluck daughter cells for five days without a break. Fortunately, the editorial noted, the effort paid off. Daughters of old cells were 40 to 200 times more likely to lose a marker gene than daughters of young cells. And subsequent losses of heterozygosity [LOH] also increased in frequency. In this way, the researchers uncovered an age-dependent, genetic instability switch in yeast.

LOH was observed in a majority of the pedigrees: 25 of 40 mothers produced at least one LOH event. Those that did not were generally short-lived. Together these results demonstrate that there is an age-induced onset of genomic instability in S. cerevisiae. Once an LOH event occurs in a pedigree, additional LOH is observed at a higher frequency for the duration of the mother s life span. This suggests that as mother cells age, there is a switch from a state with a low spontaneous rate of LOH to a state of increased genomic instability.

Overall, these data suggest that the onset and subsequent increased frequency of age-induced LOH operate on a different clock than does yeast replicative life-span, the editorial went on. The aging-associated genetic instability is thus distinct from the age-induced LOH we observed. We characterized this LOH by examining whether these events were the result of chromosome loss. Thus, age-induced LOH is likely initiated by chromosomal damage.

Next, the Seattle researchers asked rhetorically whether this DNA-instability switch contributes to yeast aging. It appears that there are at least two independent clocks in yeast cells, they put it. One determines life-span; the other controls the DNA-instability switch. In mammals, this distinction may not be as clear-cut because, unlike yeast, rogue mutant cells can kill the organism by forming tumors.

Of course, yeast may surprise us with a new mechanism, Sinclair suggested. Amid this speculation, one thing is certain: Only when we know the underlying causes of this phenomenon can we truly predict how relevant it will be to humans. But if history is anything to go by, he continued, we can look forward to learning more lessons about aging and cancer from this fungus.

The McMurray and Gottschling paper ventures, Our results provide predictions about the mechanisms that underlie age-related genomic instability in eukaryotic cells human, murine, yeast as well as a model system to test them. Ultimately, the team concluded, deeper understanding of this phenomenon in yeast may help to solve the link between oncogenesis and age in humans.