Sci. Aging Knowl. Environ., 3 August 2005
Not a Chip off the Old Block
Study identifies unexpected function for mammalian version of yeast longevity protein
Like a headstrong teen who refuses to enter the family accounting business and joins a rock band instead, the mammalian protein SIRT1 breaks with its relatives, according to a new study. SIRT1's kin in yeast promotes cell division, but the protein prods mouse cells to abandon reproduction. The work reveals SIRT1's previously unknown role in handling long-lasting stress.
Boosting yeast cells' output of a protein called Sir2p increases the number of times they can divide, a gauge of fungal life span (see Kaeberlein Perspective). Cranking up the worm and fly versions of Sir2p also prolongs life, piquing scientists' interest in the protein's mammalian variants. One of these, SIRT1, spurs cells to ditch fat (see "Counterattack"), but researchers don't know whether it stretches survival. They didn't suspect it influenced cellular senescence, a semidormant state in which cells lose the ability to divide. But cancer biologist Fred Alt of Harvard Medical School in Boston and colleagues chanced on such a link.
The researchers were investigating mouse connective-tissue cells that lack the gene for SIRT1. Normal cells stopped duplicating after doubling five to eight times, but the SIRT1-deficient cells kept multiplying. That difference suggested that SIRT1 prompts senescence. To test that possibility, the scientists allowed colonies of SIRT1-lacking mouse connective-tissue cells to double seven times. Reinserting the SIRT1 gene at that point stalled the cells' reproduction. The team then turned to mouse cells that make SIRT1 and engineered them to carry a molecular switch that allowed the researchers to delete the gene. Flipping the switch when the colonies were entering senescence permitted division to resume.
Because damage from destructive compounds called reactive oxygen species (ROS) triggers rodent cells to senesce, the researchers wanted to determine whether SIRT1 controls cell's reactions to this stress. They reared mouse cells with moderate amounts of the ROS hydrogen peroxide. SIRT1-lacking cells duplicated faster than did control cells, meaning they had evaded senescence. Cancer-causing genetic glitches usually goad cells to senesce, and the team discovered that SIRT1-lacking cells respond normally to this DNA damage. Those findings suggest that SIRT1 helps cells respond to protracted, low-level stress, not to sudden genetic injuries. Other studies indicate that Sir2p promotes cell division in yeast, but the current work shows that SIRT1 has the opposite effect in this type of mouse cell. Many of SIRT1's targets don't exist in yeast, so it makes sense that Sir2p and SIRT1 don't perform the same job, says Alt: "The protein has evolved to take on different functions in a different system."
The findings are "thought-provoking" but "puzzling" because they don't jibe with previous results for the Sir2 proteins, says molecular biologist Leonard Guarente of the Massachusetts Institute of Technology. Before we can conclude that SIRT1 is behaving differently, he says, we need to determine whether the effect is a quirk of mouse connective-tissue cells. Understanding how SIRT1 helps cells respond to oxidative damage might allow researchers to determine whether the protein affects aging, says molecular biologist Shin-Ichiro Imai of Washington University in St. Louis, Missouri. Further work might confirm whether SIRT1 has gone its own way.
August 3, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150