Biochemical clues to long lifespan revealed

Findings extend longevity research from yeast and worms to mammals

Researchers at Children’s Hospital Boston have discovered how two key cellular influences on lifespan work together, providing insights that may help reveal aging mechanisms in humans. The findings extend longevity research from yeast and worms into mammals, and suggest that longer life results, at least in part, from biochemical interactions that boost cells’ ability to resist environmental stresses while inhibiting them from committing suicide. The study appears in the February 19th Science Express, the online edition of the journal Science.

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 putting cell replication on hold, giving cells more time to perform the detoxification and repair process.

Greenberg, who holds a doctorate in biochemistry and is also a professor of neurology and neurobiology at Harvard Medical School, believes that bolstering a cell’s resistance to oxidative stress may help keep age-related disorders in check. He notes that the interaction between Sir2 and FOXO reduced the death of nerve cells, suggesting a possible strategy for reversing age-related nerve-cell degeneration, such as occurs in Alzheimer’s disease. The Sir2-FOXO interaction may also inhibit tumor formation, since DNA damage in cells can make them cancerous.

“If you have molecules that come together to mediate resistance to environmental stresses that cause aging, one might be able to come up with drugs that would affect this interaction and slow the aging process,” Greenberg says.

The research was supported by the Ellison Medical Foundation, the National Institutes of Health, and the F.M. Kirby Foundation.

Children’s Hospital Boston is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults for more than 130 years. More than 500 scientists, including seven members of the National Academy of Sciences, nine members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Children’s research community. Children’s is the primary pediatric teaching affiliate of Harvard Medical School.

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