Sci. Aging Knowl. Environ., 5 March 2003
Live Long and Ferment
Antioxidant enzyme helps yeast live to ripe old age
Key Words: aconitase superoxide stationary phase postdiauxic phase
Comedian George Burns, who lived to be 100, ascribed his longevity to frequent dates with younger women and plenty of martinis and cigars. Researchers haven't confirmed his recipe for survival, but they are beginning to uncover what makes mutant organisms live extra-long. A new study of persistent yeast shows that two longevity-promoting pathways enlist an enzyme that neutralizes cell-wrecking oxidants.
Scientists have totted up a list of genes that, when overactive or crippled, extend the life of model organisms (see Genes/Interventions Database), but they know little about which biochemical changes provoked by these mutations boost longevity. One possible elixir is Sod2, an enzyme that squelches destructive oxidants spawned by metabolism (see "The Two Faces of Oxygen"): For example, increasing Sod2 production makes flies live longer. In previous work on yeast, molecular geneticist Valter Longo of the University of Southern California, Los Angeles, and colleagues found that disabling a gene called SCH9 triples longevity--measured as survival time rather than fecundity, which some researchers use to clock yeast life span. Data from another lab hint at the mechanism: Genes that are suppressed by SCH9 crank up amounts of Sod2p.
To determine whether Sod2p rejuvenates yeast, the researchers disabled different combinations of the SOD2 and SCH9 genes and measured how long cells lived. A cell without working versions of Sod2p and Sch9p lasts no longer than normal, suggesting that the antioxidant enzyme is necessary for the life extension conferred by an SCH9 mutation. Next, the researchers tested whether Sod2p alone produced the increase in life span. Yeast with normal SCH9 that were engineered to make twice the usual amount of the enzyme lived only slightly longer than normal, however. This finding suggests that disabling SCH9 not only boosts Sod2p production, it rouses other cellular defenses that lengthen life, Longo says.
The researchers scrutinized another longevity gene, RAS2, that might also recruit Sod2p. The team showed that eliminating this gene doubled yeast survival, confirming that it normally limits life span. Other investigators have found that sabotaging RAS2 shortens yeast life, Longo notes, but they measured life span by the number of times a cell reproduces instead of by how long it survives. He says that his method better mimics how yeast age in nature. To determine whether this stretched life span depends on Sod2p, the researchers gutted RAS2 and SOD2. The altered yeast outlived normal cells by only 30%, suggesting that Sod2p was helping prolong the life span of the ras2 mutants. Results from both parts of the study show that two life-extending pathways in yeast--one involving RAS2 and the other involving SCH9--add time by boosting quantities of Sod2p.
The researchers "show that Sod proteins are very important for longevity," says geneticist Cynthia Kenyon of the University of California, San Francisco. Longo notes that a counterpart of SCH9 functions in the insulin/insulin-like growth factor-1 pathway that controls life span in worms, flies, and mice (see "One for All"). Only further investigation will show whether Sod2 does for animals what a good martini did for George Burns.
March 5, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150