Previous studies in yeast and worms pinpointed a gene known as Sir2 as a key regulator of lifespan: deleting Sir2 limits lifespan, and extra copies lengthen it. Sir2 has a counterpart in mammals, but until now, very little was known about how it worked or what it had to do with aging. Working with mouse cells, researchers led by Anne Brunet, a postdoctoral fellow in neuroscience at Children's Hospital who is now at Stanford University, discovered that Sir2 works by regulating a group of proteins known as FOXO transcription factors. FOXO proteins have also been linked with longevity; they control the expression of genes that regulate cell suicide, and also enable the cell to resist oxidative stress, or chemical stresses that can disrupt the cell's DNA, or genetic blueprint.
"Aging involves damage to cells," says Dr. Michael E. Greenberg, director of Children's Program in Neurobiology and senior investigator on the study. "If you reduce oxidative stress, you get less aging."
The Children's team found that in the presence of oxidative stress, Sir2 promoted the ability of at least one FOXO protein, FOXO3, to provide stress resistance while suppressing its ability to induce cell death. In mammals, FOXO proteins confer stress resistance by triggering reactions that detoxify the damaging chemicals, known as free radicals. This leads to the repair of DNA damage while
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Contact: Susan Craig
susan.craig@childrens.harvard.edu
617-355-8834
Children's Hospital Boston
19-Feb-2004