Sci. Aging Knowl. Environ., 23 November 2005
Shortchanged by Sir2
Longevity protein cuts off yeast survival
Sir2 giveth and Sir2 taketh away. The yeast protein and its relatives in other organisms stretch longevity, previous studies have found. But new work suggests that, under harsh conditions, Sir2 impedes yeast survival.
Researchers track aging in the budding yeast Saccharomyces cerevisiae in at least two ways. Replicative life span indicates how many new cells it spawns. Chronological life span refers to how long a nondividing cell survives. These two types of longevity approximate aspects of our cells' aging, according to some scientists. Chronological life span is relevant for cells that don't reproduce in maturity, and replicative life span for cells that split throughout an organism's life, such as those in the intestinal lining and bone marrow. Extra amounts of the worm and fly versions of the protein Sir2 extend longevity in those creatures. The protein also boosts the replicative life span of yeast cells (see Kaeberlein Perspective), but the role of Sir2 in the fungus's chronological life span remains uncertain.
To find out, geneticist Valter Longo of the University of Southern California in Los Angeles and colleagues measured survival of two strains of hardy mutant yeast. One strain persists twice as long as normal, the other three times as long. Sir2 did have an impact on chronological life span, the researchers discovered, but in an unexpected way. Removing it increased longevity even further--up to five times the normal value. Losing Sir2 muddles a cell's mating type, or sex, and leaves it sterile, which might affect life span. So the researchers deleted one of the genes that help determine mating type. The change restored the ability to mate but didn't alter longevity.
To explore why the Sir2-lacking cells lasted longer, the researchers gauged their resistance to stress. Cells without Sir2 endured heat and damaging reactive oxygen species better than did control cells. Previous work indicates that Sir2 prompts DNA repair in dividing cells. The researchers gauged the enzyme's effects on chronologically aging cells by determining how often a particular gene changed. The mutation rate climbed over time in control cells but remained level in yeast missing Sir2. That result suggests that, in contrast to Sir2's behavior in reproducing cells, the protein might foster rather than limit mutations in nonreplicating cells, the researchers concluded. They then used microarrays to gauge gene activity in the yeast. Sir2-deficient cells cranked up the activity of genes that mend DNA and turned down genes that inhibit stress-fighting mechenisms. Overall, the results suggest that although Sir2 enhances replicative life span, it thwarts changes--such as higher stress resistance--that prep the cell for long-term survival, Longo says. The work implies that Sir2's equivalents in other creatures might also have a mixed effect on persistence, he adds.
The study clarifies how yeast cells regulate their survival, but whether the results reveal anything about aging in flies, worms, or mammals is uncertain, says molecular biologist Shin-Ichiro Imai of Washington University in St. Louis, Missouri. Molecular biologist Leonard Guarente of the Massachusetts Institute of Technology in Cambridge says he doesn't buy the finding. It contradicts previous work showing that the worm version of Sir2 promotes survival in nematodes, which consist mainly of nondividing cells. Therefore, the results might apply only to these rare, extremely long-lived yeast mutants, he says. He wants to see further experiments to rule out Sir2's impact on mating. Although the researchers deleted one of the mating-type genes in one experiment, they need to remove the gene consistently to eliminate this potentially confounding factor, he says. Further work might confirm whether Sir2 plays both sides when it comes to survival.
November 23, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150